Widened Scope of Drug Repurposing/Chiral Switches, Elements of Secondary Pharmaceuticals: The Quinine/Quinidine Case

Abstract

Drug repurposing to new medical uses and chiral switches are elements of secondary pharmaceuticals. This article focuses on drug repurposing/chiral switches of the diastereomeric quasi-enantiomeric antimalarial quinine and antiarrhythmic quinidine, based on the histories of these drugs (1638–2022), applying a widened scope. Quinine, an essential medicine, changed the world. Drug repurposing is a strategy for identifying new uses for approved or investigational drugs outside the scope of the original medical indications. Potential drugs are not included in the definition of drug repurposing. Drug repurposing may be within or outside the therapeutic group, e.g., quinidine to quinine repurposing, from treatment of arrhythmia or severe malaria to uncomplicated malaria. The scope of chiral switches included racemate to single enantiomer and other switches of the status of chirality, e.g., racemate and quasi-racemate to scalemic mixtures. There are 16 quinine/quinidine stereoisomers. Given the multiple pharmacological activities of Cinchona alkaloid stereoisomers, this article calls for subjecting them to comprehensive drug repurposing/chiral switch searches for new medical uses.

Graphical abstract

Keywords::

• chiral switch
• Cinchona alkaloids
• diastereomeric interactions of enantiomers
• drug repurposing
• patents
• Plasmodium falciparum malaria
• quinidine
• quinine
• secondary pharmaceuticals
• stereoisomer

The Cinchona alkaloids quinine and quinidine (Figure 1) have been playing pioneering and lasting remarkable roles in medicine, stereochemistry (including chirality), chiral catalysis, chiral recognition and asymmetric synthesis and as chiral resolving agents [1–7]. Quinine and quinidine are highlighted in the scientific background paper released by The Nobel Committee for Chemistry (2021) [3] as the first organic catalysts for asymmetric synthesis, producing enantiomeric products. The purification of diastereomers of quinine (excluding enantiomers) by crystallization, a key task, is considered a classic in the history of purification of natural products [8]. The quinine and quinidine bases form diastereomeric salts in the resolution of racemic acids into single enantiomers.

Figure 1. Chemical structures of Cinchona alkaloids.

The IUPAC names of quinine and quinidine are (R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol and (S)-[(2R,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol, respectively. Note that the numbering of atoms in the IUPAC names differs from the conventional numbering of the atoms of quinine and quinidine.

Quinine [hydrochloride (injection), sulfate (tablet) and bisulfate (tablet)] is listed in the 22nd WHO Model List of Essential Medicines, as an antimalarial medicine for curative treatment (but not for chemoprevention) “for use only in the management of severe malaria, and should be used in combination with doxycycline” [9]. Quinine and quinidine were included in the WHO first Model List of Essential Medicines 1977 titled “The selection of essential drugs: report of a WHO expert committee” as antimalarial and antiarrhythmic drugs, respectively [10]. Quinidine was included in the WHO 12th list 2001, but was not included in the corresponding WHO lists, at least since the 18th list 2013. Quinine was listed among the 46 top pharmaceuticals that changed the world [11]. Quinine and quinidine served as primary pharmaceuticals both in the era prior to US drug regulation (1638–1938) and in the US drug regulation era (1938–2022).

The present article focuses on new medical uses and chiral switches (two elements of secondary pharmaceuticals) of quinine and quinidine. The Court of Appeal of England and Wales stated the following in 2023 in the Lyrica (pregabalin) judgment [12]:

“It has increasingly been recognised over the past 30 years or so that it is important to find new uses for existing medicines. Existing medicines have the advantage that they are known compounds which have been shown to have acceptable safety profiles, and therefore need much less testing from that perspective. Experience shows that a compound which has therapeutic benefit in one application not infrequently turns out to have therapeutic benefit in another application (sometimes more than one other application) which may be quite different to the first application. Thus there is significant potential for, and value in, finding such second (and third, etc.) medical uses. Discovering such second medical uses requires difficult and expensive research, however. How is such research to be funded? The answer which has been provided by the European patent system is to grant patents for second (and subsequent) medical uses of known compounds. The monopoly thus conferred on the inventor who finds the second medical use provides the return on the investment required to fund the research.”

The discovery of new medical uses has been explored by drug repurposing, a strategy highlighted during the recent coronavirus disease 2019 pandemic [13]. “Drug repurposing (also called drug repositioning, reprofiling or re-tasking) is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication” [14]. The benefits of the drug repurposing strategy are “to move straight to clinical trials for the new indication, bypassing the costly and lengthy discovery and early-stage development research that is needed for [the approval of] completely new drugs” [15]. Drug repurposing has recently been reviewed [16,17]. A regulatory perspective of second medical use, including drug repurposing, has recently been outlined [18]. In contrast to drug repurposing, the strategy of chiral switches has been controversial [19]. ‘Chiral switch’ is a switch of a chiral drug to a stereoisomeric drug which comprises a switch in the status of chirality (Table 1) [20–23]. Cases of switches in the status of chirality are given below. This definition, which is applicable to drugs, differs from the following definition of ‘chiroptical molecular switch’ submitted by Browne and Feringa [24]: “Switching between – chiral – molecular states is based on bistability, that is a molecule exists in two distinct forms A and B and each state can be converted to the other state reversibly upon application of an external stimulus.” The following definition of the term ‘chiral switch’ for conversion of one enantiomer into the opposite one, was introduced by Baglai, et al.: “a sequence of operations that alternate between equilibrium and non-equilibrium conditions to switch the absolute configuration of a chiral center” [25]. A chiral switch of a drug does not mean that a chiral drug that has undergone a chiral switch (e.g., a racemate) has previously been marketed. A chiral switch may operate just at the level of intellectual property (e.g., Lipitor and Plavix) [26].

Table 1. Definitions of terms.

Term	Definition	Ref.
Biopiracy	The appropriation and commercialization of indigenous technologies without adequate permission, acknowledgment or compensation	[27]
Chiral switch	A switch of a chiral drug to a stereoisomeric drug which comprises a switch in the status of chirality, e.g., racemate to single enantiomer, epimers to single enantiomer	[20–23]
Drug repurposing	A strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication	[14]
Enantiomer patent	A patent that claims a single enantiomer of a chiral drug that has been claimed previously in the corresponding basic (broader) patent as a racemate or as a mixture of diastereomers	[19]
Evergreening	Intellectual property-based evergreening is a business strategy to extend the duration of the effective protection derived or derivable from a portfolio of intellectual property rights in order to increase the appropriability of an innovation or a set of business-related innovations or technologies	[19]
Me-too drug	A drug within the same chemical class as another already on the market	[19]
Patent troll	A pejorative term for a company that uses a portfolio of patents not to produce products but solely to collect licensing fees or settlements on patent infringement from other companies	[27]
Obvious-to-try	A patentability criterion for establishing prima facie obviousness wherein it is examined whether a person skilled in the art would have possessed any reasonable expectation of success of obtaining a beneficial technical effect of the claimed invention	[19]
Pejorative	Expressing disapproval or criticism
Product hopping	The process by which a brand, as the patents on an older branded drug are expiring, uses its current dominant market position to switch doctors, pharmacists, and consumers to a newer version of the same (or similar) drug with later-expiring patents	[27]
Quasi-diastereomers	A pair of stereoisomers that are diastereomeric at a certain functionality
Quasi-enantiomers	A pair of diastereomers that are enantiomeric at a certain functionality	[32]
Quasi-racemate	An equimolar mixture of a pair of quasi-enantiomers	[32]
Quasi-scalemic mixture	A mixture of paired quasi-enantiomers that is neither a quasi-racemic mixture nor a mixture of pure quasi-enantiomers
Scalemic mixture (scalemate)	A mixture of paired enantiomers that is neither a racemic mixture (ee = 0) nor a mixture of pure enantiomers (ee = 1)
Secondary pharmaceutical patent	A patent that protects a range of aspects related to but other than the direct active pharmaceutical ingredient protected by the corresponding primary pharmaceutical patent	[19]
Teaching away	A reference may be said to teach away when a person skilled in the art, upon reading the reference, would be discouraged from following the path set out in the reference or would be led in a direction divergent from the path that was taken by the applicant	[27]
Unexpected results	A term used to assess the nonobviousness of a claimed invention; it needs to be shown to a nonobvious extent that the results were superior compared with the prior art, to a nonobvious extent	[19]

ee: Enantiomeric excess.

Enantiomer patent, a type of secondary pharmaceutical patents, is a patent that claims a single enantiomer of a chiral drug that has been claimed previously in the corresponding basic (broader) patent as a racemate or as a mixture of diastereomers. Enantiomer patents have been under attack, using the negative connotation terms ‘evergreening’, ‘product hopping’, ‘me-too’, ‘biopiracy’ and ‘pejorative’ and characterizing these patents as ‘patent troll’ and ‘obvious-to-try’ (Table 1) [19]. It has been argued that chiral switches and their enantiomer patents are ‘obvious to try’, a doctrine that must prevail over the doctrine of ‘unexpected results’, rendering these patents obvious and thus not valid. However, the arguments against chiral switches and enantiomer patents have been rebuffed. The ‘teaching away’ defense of nonobviousness (Table 1) of enantiomer patents and chiral switches (due to ‘unexpected results’) should be continued and explored in order to maintain the strategy of chiral switches [19]. The concept of the drug repurposing/chiral-switches combination strategy in drug discovery has recently been introduced [27]. Other combinations of drug repurposing (besides drug repurposing/chiral switches) with the following elements of secondary pharmaceuticals may be considered: polymorphs, salts, ether and ester compositions, dose combinations, prodrugs and metabolites. Sensing or medical diagnostics and drug devices are not within the scope of drug repurposing per se in the present context. The illustrated representative cases of application of the drug repurposing/chiral switch combination strategy [27] included mostly cases of the frequent racemic drug to single enantiomer switches, previously known as ‘racemic switches’ [20]. It should be noted that the scope of chiral switches is not restricted to racemate to single enantiomer switches. “The essential criterion of a chiral switch is a change in the status of chirality” [21,22]. This criterion is fulfilled in the switch of stereogenic diastereomer D₁ to stereogenic D₂, in which chiral switch(es) of stereodescriptors take place. Another scenario of a chiral switch is the switch of a mixture of diastereomers to a single diastereomer/enantiomer. A case in point is the chiral switch of the SCH 31925 mixture [28] of the (1S,3S,5S,10S,12R) and (1S,3S,5S,10S,12S) diastereomers (epimers) to the ACE inhibitor drug ramipril (Altace^®), a (1S,3S,5S,10S,12S) enantiomer (Figure 2). Ramipril is indicated for hypertension, reduction of the risk of myocardial infraction, stroke and death from cardiovascular causes and heart failure post-myocardial infarction. Overlooked precedents of the chiral switch D₁ to D₂ scenario are the drug repurposing/chiral switches of the Cinchona alkaloid drugs quinine and quinidine. Quinine and quinidine are diastereomers with stereodescriptors (1S,3R,4S,8S,9R) and (1S,3R,4S,8R,9S), respectively (Figure 1) [29,30]. They are enantiomeric (also known as quasi-enantiomeric) at the β-hydroxyamine functionality (C-8 and C-9) (Table 1) [31,32 (p. 1205)]. Although quinine and quinidine are diastereomers, “they produce enantiomeric products, a characteristic that has been used with much success in asymmetric catalysis” [3]. Repurposing of quinine to quinidine and quinidine to quinine are therefore chiral switches [21,26,33–36]. The Cinchona alkaloids cinchonidine [absolute configuration (1S,3R,4S,8S,9R)] and cinchonine [absolute configuration (1S,3R,4S,8R,9S)] are also considered a pair of quasi-enantiomers (Figure 1) [30]. We analyze here the application of the drug repurposing/chiral-switch combination of quinine to quinidine and quinidine to quinine. The idea of a quinine to quinidine repurposing/chiral switch has previously been put forward [21].

Figure 2. Chiral switch of the SCH 31925 mixture of diastereomers (epimers) to ramipril.

Many definitions of the term ‘drug repurposing’ (also known as drug repositioning, reprofiling or retasking) have been proposed [37]. We use in this article the following definition: “drug repurposing … is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication” (Table 1) [14]. The emphasis in this definition is on the regulatory term ‘investigational drug’, which is defined as a substance that has been tested in the laboratory and has been approved by the US FDA (and/or by another regulatory authority) for testing in people [38]. Drugs administered in the predrug regulation era (prior to 1938) may serve as starting points for drug repurposing in the drug regulation era. Original regulated drugs used off-label for specific indications should not qualify for drug repurposing. Sporadic, small-scale clinical trials in the preregulated era cannot be considered eligible for drug repurposing. By contrast, extensive use of an unofficially recognized original drug is a sufficient requisite. Therefore, a substance that has undergone sporadic, unauthorized ‘clinical trials’ does not qualify for drug repurposing.

The analysis of the rich history of the repurposing of quinine to quinidine and vice versa may be loosely divided into two periods: (i) the era prior to US drug regulation, from the 1638 discovery of Cinchona tree bark (“Fever Tree”), originally as a remedy to treat fever and since the 1860s for the treatment of malaria [39–41], to enacting the US Food, Drug and Cosmetic Act (FD&C Act) in 1938; (ii) the US drug regulation era (1938–2022). The 1938 FD&C Act required new drugs to be tested for safety before authorization for marketing.

The era prior to US drug regulation (1638–1938)

Cinchona bark (quina-quina) was officially introduced into the London Pharmacopoeia (also known as British Pharmacopoeia since 1864) in 1677 as ‘Cortex Peruanus’ [40]. “Throughout the mid-1600s to mid-1800s quinine bark was the primary treatment for malaria and it evidences remarkable results. It was also used for fever, indigestion, mouth and throat diseases, and cancer” [42]. The alkaloid quinine was extracted from Cinchona bark and root, isolated and characterized in 1820. ‘Purified’ quinine replaced Cinchona bark as the standard treatment for malaria [43].

Quinidine was first isolated from extracts of Cinchona bark and named by Henry and Delondre in 1833. Van Heijningen isolated quinidine in 1849 as a byproduct of the preparation of quinine and named it ‘beta-chinin’ [39]. Bussy and Guibourt identified quinidine sulfate in a sample of quinine sulfate in 1852 [44,45]. Pasteur showed in 1853 that the previously reported quinidine samples were actually mixtures of two alkaloids. He purified quinidine (‘chinidine’) as a distinct isomer of quinine based (inter alia) on crystalline forms, solubility and rotating polarized light: (+)-quinidine versus (–)-quinine [46,47]. During the second half of the 19th century, there were clinical experiences with quinidine, when it was extensively employed in cases of malaria and as an antipyretic in acute infectious diseases [48].

The four Cinchona alkaloids, quinine, quinidine, cinchonidine and cinchonine (Figure 1), were found to be effective against malaria with comparable efficiency in one of the earliest clinical trials (1866–1868) [40,41,49,50]. “In the year 1866, the Madras Government appointed a Medical Commission to test the respective efficacy in the treatment of fever of quinine, quinidine, cinchonine and cinchonidine” [49]. From the Report (published in 1891) it appears that the total number of cases of paroxysmal malarious fevers treated was 2472, namely, 846 treated with quinine, 664 trated with quinidine, 559 treated with cinchonine and 403 treated with cinchonidine. Of these 2472 cases, 2445 were cured and 27 were not. The differences in the remedial value of the four alkaloids were deduced from these experiments [49] according to the ratio of failures per 1000 as follows: quinidine 6, quinine 7, cinchonidine 10, cinchonine 23.

The results of the ‘controlled clinical trials’ [40] established that there was no preference of quinine over quinidine in treating malaria in terms of efficacy and toxicity. In spite of the recognized equivalence in antimalarial efficacy and similar toxicity of quinine and quinidine, “quinidine sulphate, however, has been official in the US Pharmacopeia since 1884 having apparently been included because of its antimalarial efficacy” [50]. After 1890, a switch in the supply from South American to Javan Cinchona bark, which contained a higher percentage of quinine compared with quinidine, led to the dominant use of quinine for the treatment of malaria [43], which lasted through the remaining years of the predrug regulation era. A clinical comparison study of quinine and quinidine sponsored by the British Medical Research Council in 1925 concluded that “the immediate effect of quinidine bisulphate in malaria is as good, or slightly better than, that of quinine bisulphate” [51]. A notable 1931 clinical study of the efficacy of quinidine versus quinine in malaria concluded that the antimalarial efficacy of quinidine was confirmed, with no inferiority of quinidine versus quinine: “quinidine is recommended for trial as a quinine substitute in cases of asthmatic, coryzal or urticarial reaction to quinine, or in cases of malaria in which the response to quinine is poor” [50].

“Quinine was available/marketed in the US since before 1906, when the [original Pure] FD&C Act was enacted. Four New Drug Applications (NDAs) were found in the [old] FDA records, none of the NDAs was for the treatment of malaria [and cardiac arrhythmias]. One possible explanation for the absence of an NDA for malaria is that quinine was already available OTC for the treatment of malaria, and no one submitted a new drug application for this use” [42]. (See Qualaquin, NDA#021799, Drugs@FDA: FDA-Approved Drugs, 12 August 2005. Label, Summary Review, Medical Review(s), Chemistry Review(s), and Administrative Document(s) & Correspondence). “Quinidine was the first medicine used in the therapy of heart arrhythmias” [52]. The effect of quinidine on cardiac function was first reported by Wenckebach in 1914 [40,53,54]. “Walter Frey, in 1918, conducted the first systematic study of the effect of cinchona alkaloids in patients with atrial fibrillation and found that quinidine was more effective than quinine in cardioverting to sinus rhythm” [40]. “For years quinidine was used as the drug of choice for atrial fibrillation (AF), atrial flutter, paroxysmal tachycardia (atrial, nodal and ventricular origin) and ventricular fibrillation (VF)” [52]. The question whether quinine and quinidine have undergone drug repurposing/chiral switch combination in the predrug regulation era will be addressed in the overview section (vide infra).

The US drug regulation era (1938–2022)

FDA regulatory history of quinidine medicines/drugs

The FDA approval of quinidine medicines for the treatment of cardiac arrhythmia in the US drug regulation era preceded the FDA approvals of quinine and quinidine medicines for the treatment of malaria, in contrast to the corresponding use of quinine and quinidine medicines in the era prior to drug regulation. The first FDA-approved NDA containing a quinidine medicine was NDA#006320 (also known as NDA 6–320), quinidine hydrochloride injection, an antiarrhythmic drug approved circa October/November 1947 (Table 2). The approval of NDA#006320 was withdrawn by the FDA effective 2 February 1973, on the grounds that the applicant had failed to make annual reports as required by law, the applicant had advised the FDA that the new drug had never been marketed or marketing had been discontinued and the applicant had requested withdrawal [55,56].

Table 2. US FDA New Drug Applications of quinidine and quinine medicines.

Quinidine (1S,3R,4S,8R,9S)	Quinine (1S,3R,4S,8S,9R)
Formula	Formula
NDA#006320	NDA#206
Brand name: Quinidine Hydrochloride	Brand name: not available
Active ingredient: quinidine hydrochloride (injection)	Active ingredient: quinine sulfate (tablets)
FDA approval date: 1947 (withdrawn 1973)	FDA approval date: 1938
Drug classification: not available	Drug classification: not available
Indication/use: cardiac arrhythmia	Indication/use: relief of minor aches and pains
NDA#007529	NDA#227
Brand name: Quinidine Gluconate	Brand name: not available
Active ingredient: quinidine gluconate (injection)	Active ingredient: quinine sulfate
FDA approval date: 12 July 1950 (withdrawn 2019)	FDA approval date: 1938
Drug classification: New Active Ingredient	Drug classification: not available
Indication/use: cardiac arrhythmia	Indication/use: not available
NDA#007529/S-010	NDA#805
Brand name: Quinidine Gluconate	Brand name: not available
Active ingredient: quinidine gluconate (injection)	Active ingredient: quinine bisulfate (vaginal jelly)
FDA approval date: 12 June 1991 (withdrawn 2019)	FDA approval date: 1938
Supplement category: Efficacy-New Indication	Drug classification: not available
Indication/use: cardiac arrhythmia and life-threatening Plasmodium falciparum malaria	Indication/use: feminine hygienic preparation
NDA#007529/S-013	NDA#4425
Brand name: Quinidine Gluconate	Brand name: not available
Active ingredient: quinidine gluconate (injection)	Active ingredient: quinine bisulfate
FDA approval date: 7 March 1994	FDA approval date: 1938
Supplement category: labeling	Drug classification: not available
Indication/use: life-threatening Plasmodium falciparum malaria, conversion of atrial fibrillation/flutter, ventricular arrhythmia	Indication/use: not available
NDA#012796	NDA#021799
Brand name: Quinidex^®	Brand name: Qualaquin^®
Active ingredient: quinidine sulfate (tablets)	Active ingredient: quinine sulfate (capsules)
FDA approval date: 21 February 1962 (withdrawn 2007)	FDA approval date: 12 August 2005
Drug classification: New Dosage Form	Drug classification: New Formulation
Indication/use: cardiac arrhythmia	Indication/use: uncomplicated Plasmodium falciparum malaria
NDA#012796/S-049
Brand name: Quinidex Extentabs^®
Active ingredient: quinidine sulfate (extended-release tablets)
FDA approval date: 16 August 2001 (withdrawn 2007)
Supplement category: labeling
Indication/use: cardiac arrhythmia
NDA#011642
Brand name: Cardioquin^®
Active ingredient: quinidine polygalacturonate (tablets)
FDA approval date: before 1960 (withdrawn 2000)
Drug classification: not available
Indication/use: cardiac arrhythmia
NDA#011642/S-012
Brand name: Cardioquin^®
Active ingredient: quinidine polygalacturonate (tablets)
FDA approval date: 16 June 1999
Supplement category: labeling
Indication/use: cardiac arrhythmia
NDA#021879
Brand name: Nuedexta^®
Active ingredients: dextromethorphan hydrobromide, quinidine sulfate (capsules)
FDA approval date: 29 October 2010
Drug classification: New Combination
Indication/use: pseudobulbar affect (PBA)

NDA: New drug application.

On 12 July 1950, the FDA approved NDA#007529 (also known as NDA 7–529), the antiarrhythmic drug quinidine gluconate injection (Table 2) [57]. Following the 1962 Kefauver–Harris Amendment of the FD&C Act that required evidence of drug effectiveness for the stated indication, the FDA applied Drug Efficacy Study Implementation (DESI), its administrative process to consider the effectiveness of drugs that had been approved only for safety between 1938 and 1962 [58]. The FDA obtained reports from the US National Academy of Sciences–National Research Council (NAS-NRC), Drug Efficacy Study Group and from other available sources and gathered other evidence of drug effectiveness for the stated indications on several approved antiarrhythmic drugs, including NDA#006320, NDA#007529, NDA#012796 (vide infra) and NDA#011642 (vide infra), regarded as new drugs. According to the DESI report LOG No. 1237 on the Drug Efficacy Study of NDA 7–529, Quinidine Gluconate Injection (Quinidine Gluconate Ampules, U.S.P., Injection) [received by the author IA via Freedom of Information Act (FOIA) Request No. 2021–5988], the indications of NDA 7–529 were as follows: “parenteral administration of quinidine is indicated (1) when the patient with ectopic tachycardia cannot take medication by mouth because of vomiting or unconsciousness and (2) when, in the presence of very rapid heart action (especially ventricular tachycardia), it is imperative that the therapeutic effect of the quinidine be obtained as quickly as possible. In the absence of emergency, tablets quinidine sulfate, USP, should be given by mouth. The intramuscular use of quinidine has been recommended in certain cases of persistent hiccup.”

The stated indications in the US National Academy of Sciences–National Research Council report were based on the NDA 7–529 label dated 2 August 1965, provided by Eli Lilly and Company (IN, USA), the holder of the marketing authorization [55]. The DESI report provides unequivocal proof that the indications of the quinidine drug approved in 1950 had not included treatment of malaria. Indeed, the FDA announced in 1976 the following conclusion concerning the drug quinidine gluconate injection (NDA#007529): “effective for the treatment of the following conditions when oral therapy is not feasible or when rapid therapeutic effect is required: premature atrial and ventricular contractions; paroxysmal atrial tachycardia; paroxysmal AV junctional rhythm; atrial flutter; paroxysmal atrial fibrillation; established atrial fibrillation when therapy is appropriate; paroxysmal ventricular tachycardia when not associated with complete heart block; and maintenance therapy after electrical conversion of atrial fibrillation and/or flutter” [59]. Likewise, the confirmed indication did not include treatment of malaria. The FDA’s classification code for NDA#007529 is Type 2 – New Active Ingredient [57,60]. It was not considered by the FDA to be classification code Type 1 – New Molecular Entity [60] – probably because quinidine, its active moiety, had not been the first active moiety approved and marketed in the US in view of previously approved NDA#006320, quinidine hydrochloride injection.

On 21 June 1985, the US Centers for Disease Control and Prevention (CDC) addressed the use of “intravenous quinidine gluconate in the treatment of severe Plasmodium falciparum infections” [61]. The CDC noted that “recent studies from Thailand, where there is renewed interest in the use of quinidine as an antimalarial because of increasing insensitivity to quinine, have shown both oral and intravenous quinidine to be as effective as quinine in clearing parasitemia. … Quinidine gluconate is an attractive alternative to quinine dihydrochloride in the treatment of P. falciparum infections when intravenous therapy is indicated because of its ready availability in most US acute-care facilities. Because it is an unlabeled use of the drug, the Malaria Branch, Division of Parasitic Diseases, Center for Infectious Diseases, CDC, has filed an Investigational New Drug notice (IND) with the US FDA for the treatment of severe P. falciparum malaria with intravenous quinidine gluconate.” An investigational new drug is “a substance that has been tested in the laboratory and has been approved by the US FDA for testing in people” [62].

On 12 June 1991, the FDA approved NDA#007529 SUPPL-10, quinidine gluconate injection, approval type Efficacy-New Indication (Table 2) [57]. Its indications include treatment of both cardiac arrhythmias and life-threatening Plasmodium falciparum malaria. Kitchen et al. reported that “in 1991, the FDA granted labeling revision of quinidine for antimalarial purposes” [63]. FDA approval of the new indication for NDA#007529 followed the earlier 1991 recommendation by the US CDC for the “treatment of severe Plasmodium falciparum malaria with quinidine gluconate” [64].

According to the FDA, ‘severe malaria’ is characterized by “hyperparasitemia, destruction of parasitized red cells, and sequestration of red cells in small blood vessels causing end-organ dysfunction or failure” [65]. According to the glossary in the WHO guidelines for the treatment of malaria, ‘severe falciparum malaria’ is “acute falciparum malaria with signs of severity and/or evidence of vital organ dysfunction,” whereas ‘uncomplicated malaria’ is “symptomatic malaria parasitaemia with no signs of severity and/or evidence of vital organ dysfunction” [66]. “For epidemiological purposes, ‘severe falciparum malaria’ is defined as one or more of the following, occurring in the absence of an identified alternative cause and in the presence of P. falciparum asexual parasitaemia. o impaired consciousness o prostration o multiple convulsions o acidosis o hypoglycaemia o severe malarial anaemia o renal impairment o jaundice o pulmonary oedema o significant bleeding o shock o hyperparasitaemia.” Thus, the definitions of severe P. falciparum malaria and uncomplicated P. falciparum malaria differ significantly. According to USP Di 1997: Drug Information for the Health Care Professional (17th Ed, Vol 1), United States Pharmacopoeia (1997), Quinidine’s Category is antiarrhythmic; antimalarial [67]. The FDA withdrew approval of NDA#007529 (including its approved supplements) effective 9 October 2019, after the applicant, Eli Lilly and Company, notified the agency that the drug product was no longer marketed and requested that approval of the application be withdrawn [68]. “While the reasons for discontinuation [of quinidine] have not been publicly disclosed, limited profitability due to low demand in the US is likely the primary factor. Historically, its primary use in the US has been treating atrial and ventricular arrhythmias, not malaria, and use has decreased with the adoption of safer antiarrhythmic drugs” [69].

On 7 March 1994, the FDA approved NDA#007529 SUPPL-13, Quinidine Gluconate Injection (Table 2), for the following indications: ”1. Treatment of life-threatening Plasmodium falciparum malaria. 2. Conversion of atrial fibrillation/flutter. … 3. Treatment of ventricular arrhythmias” [70]. The quinidine formulation NDA#012796 (also known as NDA 12–796), entitled Quinidex Extentabs Tablets, active ingredient quinidine sulfate, extended-release tablets, which was included in the FDA’s 1972 Notice on Certain Anti-Arrhythmic Drugs [55], should not be overlooked. The FDA approved NDA#012796 on 21 February 1962 (Table 2) [71]. The US trademark Quinidex Extentabs was registered on 21 July 1964 (filing date 6 December 1963). Its Goods and Services were described as follows: “Antiarrhythmic Medicinal Preparation for Use in Cardiac Therapy” [72]. The US trademark Quinidex was registered only on 22 October 2002 (filing date 7 February 2002). Its Goods and Services were described as follows: “Antiarrhythmic Cardiovascular Pharmaceutical Preparation” [73]. According to the FDA’s 1972 notice, the indications of NDA#012796, Quinidex Extentabs, were the treatment of “premature atrial and ventricular contractions; paroxymal atrial tachycardia; paroxysmal AV junctional rhythm; atrial flutter; paroxysmal atrial fibrillation; established atrial fibrillation, when therapy is appropriate; paroxysmal ventricular tachycardia when not associated with complete heart block; maintenance therapy after electrical conversion of atrial fibrillation and/or flutter” [55]. On 16 August 2001, the FDA approved NDA#012796 SUPPL-49, Quinidex Extentabs Tablets, active ingredient quinidine sulfate (Table 2). The description of the approved label states: “quinidine is an antimalarial schizonticide and an antiarrhythmic agent with Class Ia activity” [71]. However, the indications and usage refer only to cardiac therapy: “conversion of atrial fibrillation/flutter; reduction of frequency of relapse into atrial fibrillation/flutter; suppression of ventricular arrhythmias.” Remarkably, indications for the treatment of malaria are absent. The FDA announced the withdrawal of approval of NDA 12–796, Quinidex Extentabs (quinidine sulfate extended-release tablets, USP), effective 7 November 2007 [74].

Following the DESI administrative process for NDA#006320 and NDA#007529 (vide supra), the FDA referred also to the antiarrhythmic drug Cardioquin, NDA#011642 (also known as NDA 11–642), quinidine polygalacturonate, tablets, which approved before 1960 (Table 2) [55,75]. Cardioquin is a polymer of quinidine and galacturonic acid. Its indications were identical to those of Quinidex. The FDA concluded that Cardioquin was also effective for these indications [55]. The corresponding NDA#011642 SUPPL-12, approved on 16 June 1999 (Table 2), contained the following indications: “conversion of atrial fibrillation/flutter; reduction of frequency of relapse into atrial fibrillation/flutter; suppression of ventricular arrhythmias” [75]. Cardioquin was discontinued effective 30 September 2000.

Following the 2005 ‘breakthrough’ of the first FDA approval of an antimalarial quinine drug 367 years since the discovery of the ‘fever tree’ and 67 years since the birth of the US drug regulation era, the FDA encountered a twist in the quinine–quinidine saga. On 29 October 2010, the FDA approved the repurposed quinidine combination drug Nuedexta, NDA#021879, active ingredients dextromethorphan (DXM) hydrobromide and quinidine sulfate, capsules (Table 2) [76]. Nuedexta is a fixed-dose combination drug indicated for the treatment of neither malaria nor arrhythmia. Its FDA classification code is Type 4 – New Combination [60]. The approved indication for Nuedexta was “the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurologic conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying” [76]. DXM hydrobromide is the pharmacologically active ingredient of Nuedexta that acts on the CNS. “DXM was approved by the FDA in 1958 and introduced as a non-prescription replacement for codeine-based antitussives under the brand name Romilar” [77] but was withdrawn from the US market in 1973. Quinidine sulfate is a specific inhibitor of CYP2D6-dependent oxidative metabolism by which DXM is rapidly converted to dextrorphan, a metabolite not considered to be active against PBA. Quinidine, a potent inhibitor of CYP2D6, is “given in combination with DXM to competitively inhibit the metabolism of DXM to DXO [dextrorphan]“ [76]. Quinidine also increases the duration of action of DXM by prolonging its half-life.

FDA regulatory history of quinine medicines/drugs

The first FDA-approved NDAs containing quinine as an active ingredient were NDA#206 (quinine sulfate), NDA#227 (quinine sulfate), NDA#805 (quinine bisulfate) and NDA#4425 (quinine bisulfate) (Table 2) [42]. NDA#206 was an oral formulation (tablets), NDA#805 was a topical (vaginal jelly/powder) feminine hygienic preparation. NDA#206 was for relief of minor aches and pains. No further data were available for NDA#227 or NDA#4425. None of these NDAs was for the treatment of malaria and/or cardiac arrhythmia. All were “submitted following the 1938 amendments [of the FD&C Act] because ‘new drugs’ could not be introduced into the interstate commerce unless an application was filed that included a report the new drug was safe for use.” They were approved by the FDA based on findings of safety. All of the aforementioned NDAs were withdrawn by the FDA commissioner after the 1962 Kefauver–Harris Amendment of the FD&C Act, which required evidence of drug effectiveness for the stated indication [58].

In 1993, the FDA issued a rule for certain OTC Category II (not generally recognized as safe and effective and misbranded) and Category III (more data needed) active ingredients for which no significant comments or new data to upgrade the status of these ingredients had been submitted [78]. In that final rule, the agency determined that quinine (among other ingredients) was not generally recognized as safe and effective and was misbranded when present in OTC internal analgesic, antipyretic and antirheumatic drug products. In 1995, the FDA issued a notice of proposed rulemaking that would establish that OTC drug products containing quinine for the treatment and/or prevention of malaria were not generally recognized as safe and were misbranded. The FDA issued that notice after considering data and information on the safety of quinine [79]. In 1998, the FDA issued a final rule establishing that OTC drug products containing quinine for the treatment and/or prevention of malaria were not generally recognized as safe and were misbranded [80]. In 2004, the FDA emphasized that “while quinidine is approved in the US for the initial treatment of severe and life-threatening P. falciparum malaria,” quinine is not, and that “early and aggressive therapy of P. falciparum malaria is needed to prevent the development of hyperparasitemia and severe malaria, thereby obviating an urgent need for IV [intravenous] quinidine” [42]. The US CDC noted in its recommendation of April 1991 that “on an equimolar basis, quinidine is a more active antimalarial than quinine for P. falciparum. … Therefore, the dosage of quinidine required for the effective treatment of persons with P. falciparum malaria is lower than the dosage of quinine needed” [64].

The first FDA-approved NDA containing quinine for the treatment of malaria was NDA#021799, Qualaquin, active ingredient quinine sulfate, capsules, approved on 12 August 2005 (Table 2) [42]. Its FDA classification code was Type 5 – New Formulation [60]. “Quinidine sulfate is indicated [in this approval] only for treatment of uncomplicated Plasmodium falciparum malaria. … Quinine sulfate oral capsules are not approved for patients with severe or complicated P. falciparum malaria, [nor] for prevention of malaria [and] for the treatment or prevention of nocturnal leg cramps” [42]. As of 2005, NDA#021799 was the only antimalarial approved application for a product containing quinine. Because the incidence of malaria in the US was rare, quinine sulfate capsules in patients with malaria was ironically granted Orphan Drug Designation (ODD), with 7 years exclusivity since the day of approval, i.e., until 12 August 2012) [81]. The FDA approved quinine sulfate for the treatment of uncomplicated P. falciparum malaria in 2005 in order “to preserve the availability of quinine for the treatment of malaria while proceeding to regulate the unsafe over-the-counter use of quinine for nocturnal leg cramps” [82]. In December 2006, when a safe and effective FDA-approved quinine sulfate product (i.e., NDA#021799) became available, the FDA addressed the legal status of drug products containing quinine. The FDA concluded that “drug products containing quinine, quinine sulfate, and any other salt of quinine are new drugs that require approved applications” [81]. The FDA added: “Based on the safety and effectiveness considerations described previously, drugs containing quinine, quinine sulfate, or any other salt of quinine are not GRASE [generally recognized as safe and effective] for the treatment or prevention of malaria, leg cramps, or any other condition under section 201(p) of the [FD&C] Act. Therefore, a drug product containing any of these ingredients, alone or in combination with other drugs, is regarded as a new drug as defined in section 201(p) of the act and is subject to the requirements of section 505 of the act [New Drugs]. An approved application is required to market the product” [81]. In 2021, quinine served as a “well-documented example of significant adverse events associated with unapproved new drugs that resulted in compliance actions to remove an entire class of unapproved new drugs from the market. … As of February 2021, there are five FDA-approved quinine sulfate capsules, including four generic drug products, available in the marketplace” [83].

Overview of drug repurposing/chiral switch combination of quinine & quinidine medicines

The search for chiral switches of quinine to quinidine and quinidine to quinine in the preregulation era (1638–1938) did not reveal any evidence of chiral switches for treating either malaria or cardiac arrhythmia. Both quinine and quinidine are considered primary pharmaceuticals used for the treatment of malaria. The fact that quinine had become the dominant antimalarial drug in the late 19th century was not due to superior pharmacological properties (efficacy and/or safety) in comparison with quinidine, but rather to the fact that the Javan Cinchona plant source yielded a substantially higher percentage of quinine compared with quinidine. “Quinine was the primary alkaloid of various species of Cinchona family Rubiaceae. … Bark from cultivated plants contains 7–10% total alkaloids, and about 70% of the total is quinine” [42]. By contrast, a drug repurposing of quinidine, but not of quinine, from antimalarial use to antiarrhythmic use took place during the predrug regulation era. Thus, a drug repurposing/chiral switch combination of quinine to quinidine and quinidine to quinine did not occur during this era.

Unexpectedly, this chain of events was reversed in the US drug regulation era. In 1947–1950, the FDA approved the first formulations of a Cinchona alkaloid medicine (i.e., quinidine hydrochloride injection and quinidine gluconate injection) as antiarrhythmic drugs. In 1991, the FDA approved the introduction of a new indication for quinidine gluconate injection, adding life-threatening P. falciparum malaria therapy to cardiac arrhythmia therapy. This was a case of repurposing quinidine without a chiral switch. The first FDA approval of a quinine formulation for the treatment of malaria took place only in 2005 with Qualaquin, quinine sulfate (capsules), indicated for the treatment of uncomplicated P. falciparum malaria. This approval constituted a drug repurposing/chiral switch combination of a quinidine formulation for the treatment of cardiac arrhythmia and life-threatening P. falciparum malaria to a quinine formulation for the treatment of uncomplicated P. falciparum malaria. The first case of adaptation of the drug repurposing/chiral switch combination is the repurposing of quinine (historical, malaria) to quinidine (1947–1950, cardiac arrhythmia).

A deviation from the drug repurposing/chiral switch of quinidine for the treatment of cardiac arrhythmia and life-threatening malaria to quinine for the treatment of uncomplicated malaria took place in 2010 with the approval by the FDA of Nuedexta, a fixed combination of DXM hydrobromide and quinidine sulfate, for the treatment of PBA. In this combination drug, quinidine is neither an antiarrhythmic nor an antimalarial drug, but rather an inhibitor of the main metabolic pathway for elimination of DXM. The repurposing in this case is from the single-enantiomer quinidine to the DXM–quinidine combination of two single-enantiomer drugs.

An interesting quinine-based formulation is Quinimax, a combination drug consisting of four Cinchona alkaloids: quinine (96%), quinidine (2.64%), cinchonine (0.68%) and cinchonidine (0.68%) (as bases of hydrochloride salts) [84–86]. The therapeutic indication of Quinimax is treatment of uncomplicated malaria, particularly in cases of resistance to amino-4-quinolines [84]. A double-blind clinical trial of rectal versus intravenous quinine using the Quinimax formulation for the treatment of childhood cerebral malaria concluded that “intrarectal quinine is efficacious and could be used as an alternative treatment, especially in situations in which intravenous therapy is not feasible” [85]. The marketing authorization holder of Quinimax is Sanofi-Aventis (Paris, France). Quinimax is a registered trademark in France (registration no. 4484186, dated 11 January 2019, applicant Sanofi société anonyme). Its Goods and Services were described as follows: ”produits pharmaceutiques“ [86]. From a stereochemical point of view, Quinimax contains a ‘scalemic quasi-racemic’ mixture of quinine/quinidine (diastereomeric excess: 94.6) and a ‘quasi-racemic’ mixture of cinchonine/cinchonidine (diastereomeric excess: 0) (Table 1). The dominant Cinchona alkaloid, which is considered the ‘active ingredient’, is obviously quinine. An outline of the drug repurposing and chiral switch FDA regulatory events regarding quinine and quinidine medicines is given in Table 3.

Table 3. Drug repurposing and chiral switch regulatory events regarding quinine and quinidine medicines.

	Quinidine/quinine, indication (period/year)	Quinidine/quinine repurposing (year)	Quinidine/quinine, repurposed indication
1.	Quinidine, malaria (historical)	Repurposing (before 1938)	Quinidine, cardiac arrhythmia
2.	Quinine, malaria (historical)	Repurposing (1938)	Quinine, minor indications
3.	Quinine, malaria (historical)	Repurposing/Chiral switch (1947–1950)	Quinidine, cardiac arrhythmia
4.	Quinidine, cardiac arrhythmia (1950)	Repurposing (1991)	Quinidine, severe malaria
5.	Quinidine, cardiac arrhythmia (1950)	Repurposing/Chiral switch (2005)	Quinine, uncomplicated malaria
6.	Quinidine, severe malaria (1991)	Repurposing/Chiral switch (2005)	Quinine, uncomplicated malaria
7.	Quinidine, cardiac arrhythmia (1950)	Repurposing (2010)	Dextromethorphan + Quinidine, pseudobulbar affect

Widening the scope of the elements of the combination

Consideration of the cases of drug repurposing/chiral switches of quinine and quinidine is an opportunity to widen the scope of the drug repurposing and chiral switch elements of secondary pharmaceuticals. We refer to the definition of drug repurposing (Table 1) applied in the present article [14,27]. This definition emphasizes the regulatory aspects of drug repurposing [14]. The repurposing of quinidine for the treatment of severe P. falciparum malaria (approved in 1991) to its diastereomer quinine for the treatment of uncomplicated P. falciparum malaria (approved in 2005) is a bona fide drug repurposing/chiral switch. Thus, the scope of drug repurposing is widened. It may take place within a therapeutic group (in the present case, antimalarials). This widening of scope is consistent with the definitions of both ‘drug repurposing’ and ‘chiral switch’. Quinine was not approved for severe malaria and quinidine was not approved for uncomplicated malaria. The significant difference between ‘life-threatening’ or ‘severe’ malaria and ‘uncomplicated’ malaria is sufficient to allow acceptance of this case as a genuine example of a repurposing/chiral switch combination even though the targeted disorder (malaria), pathogen and underlying mechanism of action are the same for both medicines. Thus, regulatory aspects win over scientific wisdom in drug repurposing. Likewise, drug repurposing of the racemic drug ketamine from ‘depression’ to the single-enantiomer esketamine for ‘major depressive disorder’ is a bona fide drug repurposing/chiral switch case [27]. It should be pointed out that the repurposing of the antiarrhythmic quinidine (approved in 1950) to the antimalarial quinine (uncomplicated malaria, approved in 2005) may also be considered a drug repurposing/chiral switch.

Quinine and quinidine (Figure 1) are two diastereomers belonging to a family of 16 stereoisomers that consists of the following eight enantiomers and their paired enantiomers, respectively [30]: quinine (1S,3R,4S,8S,9R), quinidine (1S,3R,4S,8R,9S), epiC⁹quinine (also known as epiquinine) (1S,3R,4S,8S,9S), epiC⁹quinidine (also known as epiquinidine) (1S,3R,4S,8R,9R), epiC³quinine (also known as epivinylquinine) (1S,3S,4S,8S,9R), epiC³quinidine (also known as epivinylquinidine) (1S,3S,4S,8R,9S), epiN¹C⁴quinine (1R,3R,4R,8S,9R) and epiN¹C⁴quinidine (1R,3R,4R,8R,9S); paired enantiomers: quinine enantiomer (1R,3S,4R,8R,9S), quinidine enantiomer (1R,3S,4R,8S,9R), epiC⁹quinine enantiomer (1R,3S,4R,8R,9R), epiC⁹quinidine enantiomer (1R,3S,4R,8S,9S), epiC³quinine enantiomer (1R,3R,4R,8R,9S), epiC³quinidine enantiomer (1R,3R,4R,8S,9R), epiN¹C⁴quinine enantiomer (1S,3S,4S,8R,9S) and epiN¹C⁴quinidine enantiomer (1S,3S,4S,8S,9R). Note that stereoisomer epiN¹C⁴quinine is the paired enantiomer of epiC³quinidine and stereoisomer epiN¹C⁴quinidine is the paired enantiomer of epiC³quinine. The five chirality centers in quinine and quinidine (N¹,C³,C⁴,C⁸,C⁹) give rise to 2⁴ = 16 stereoisomers, not to 2⁵ = 32, because the absolute configurations of the bridgehead atoms N¹ and C⁴ are mutually dependent as a result of the rigidity of the bicyclic quinuclidine moiety. Furthermore, the racemates, the quasi-racemates (e.g., a mixture of quinine and quinidine; a 1:1 mixture of cinchonine and cinchonidine in Quinimax) and scalemic mixtures [87–89] of each of the 8 pairs of enantiomers thereof should also be considered. The enantioselective total syntheses of many of these diastereomers, including the unnatural (+) enantiomer of quinine, have been reported [90].

Claims of chiral switches of quinine and quinidine to their 14 stereoisomers (two enantiomers and 12 diastereomers) have been attempted in patent prosecutions. The 16 quinine and quinidine individual stereoisomers (stereochemically purified forms) and mixtures thereof have been claimed in US Patent 6,844,355 B2 [91], which expired on 18 January 2009 (because of failure to pay the maintenance fee), and in European Patent EP 1,240,167 A1 (application no. 00986731.8) [92] titled “Optically active isomers of quinine and quinidine and their respective biological action.” The summary of the invention of these patent applications states, “The present invention provides methods for purifying, identifying and using optically active isomers of quinine and quinidine as well as compositions comprising such optically active isomers. Such optically active isomers having desired actions on the cardiac sodium and potassium channel function substantially separable from undesirable effects on GI [gastrointestinal] motility can be useful for more effective therapy of cardiac arrhythmias. Also disclosed are methods for assaying the levels of such isomers present in the biological fluids” [91,92]. According to the Patent Cooperation Treaty preliminary examination report (PCT/12523EP/mi) of 16 October 2003, the patent application “suggests that specific enantiomers may have differential pharmacological profiles. The application showes differential activities on potassium channel inhibition and GI [gastrointestinal]-contractility between quinine and quinidine” [93]. However, on 3 July 2006, the European Patent Office Examining Division refused European patent application number 00986731.8. “The problem underlying the application may be seen in the provision of agents which exhibit differential effects of (8-vinylquinuclidine-2-yl)(6-methoxy(4-quinolyl)methan-1-ol compounds [the quinine and quinidine group of 16 stereoisomers] more or less selectively, in particular with respect to arrhythmia and gastrointestinal motility” [93]. However, “the application is not considered to meet the requirements of sufficient disclosure, novelty and inventive step,“ and did “not describe any unexpected particular pharmacological profile for any particular stereoisomer, on which an inventive step could be based.” [93]. The validity of US Patent Application 2003/023211098 A1 that led to the approved US Patent 6,844,355 B2 [91] has previously been discussed by Caner [94]. She concluded that the purified quinine and quinidine stereoisomers claimed in the patent application were not novel and their mixtures were not sufficiently described [94].

Numerous biological activities of the quinine and quinidine diastereomers have been reviewed (up to 2013) [30]. Quinine’s reported efficacy as a first-generation chemosensitizer in human leukemia cells is noted [95]. However, first-generation chemosensitizers showed “non-desirable toxicity to non-cancerous cells, were non-specific, and had low affinity to the ATP binding cassette (ABC) transporter, so that they required high doses to function in vivo” [96]. The drug repurposing/chiral switches of quinine and quinidine to their 14 diastereomers are potentially valid.

Quinidine and quinine, but not epiC⁹quinine and epiC⁹quinidine, have exhibited intermolecular diastereomeric solute–solute interactions of enantiomers, reflected in unusual NMR shielding effects and pronounced NMR chemical shift concentration and temperature dependence [89,97,98]. The pioneering discovery of self-induced nonequivalence (also known as auto-nonequivalence) phenomena – based on different NMR spectra for natural (single enantiomer), racemic and mixtures thereof of dihydroquinine – is noted [99]. Such diastereomeric interactions of enantiomers may be taken into account when considering the antimalarial and antiarrhythmic activities and future drug repurposing (efficacy and safety/toxicity) of natural, racemic, scalemic and unnatural diastereomers of the quinine and quinidine series.

The phenomenon of intermolecular diastereomeric solute–solute interactions of enantiomers deserves comments; quotations are retrieve mostly from Marom et al. [100]. Solute–solute “nonbonded interactions comprise van der Waals and electrostatic interactions, hydrogen bonding, pi-complex formation and other forms of electron donation and acceptance that are readily reversible” [32 (p. 154),100]. Dimeric interactions may serve as a model for higher molecular assemblies: “homochiral and heterochiral interactions among molecules of like constitution are unlikely to be exactly equal in magnitude, ΔG_homo≠ΔG_hetero , because the two types of aggregated are diastereomeric. The difference ΔΔG between homochiral interactions (E₊···E₊) and heterochiral interactions (E₊···E_-) is responsible for measurable differences in physical [and pharmacological] properties [between] racemates and the corresponding enantiomerically pure compounds.” [32 (p. 154),100]. E₊···E₊ and E₊···E_- reflect diastereomeric interactions (Figure 3). For a single enantiomer, only homochiral interactions are possible, whereas for a racemate, both homochiral interactions and heterochiral interactions are possible [100]. From this fundamental point of view, a racemate is not a superposition of its enantiomer constituents. By the same token, a quasi-racemate drug (e.g., a 1:1 mixture of quinine and quinidine) is not a superposition of its quasi-enantiomer constituents (quinine, quinidine) and may show improved therapeutic implications.

Figure 3. Homochiral and heterochiral interactions: enantiomers versus racemate.

Conclusion

What are the lessons of the drug repurposing/chiral switch combination of quinine and quinidine? The application of the drug repurposing/chiral switch combination strategy to quinine and quinidine, as reflected in their rich regulatory history and lessons thereof overviewed and outlined (Table 3) in the present article, provides an opportunity for future exploitation of this strategy toward new inventive secondary pharmaceuticals.

The major medical uses of quinine and quinidine (i.e., treatment of malaria and arrhythmia) were extensively practiced for many years. Beyond these applications, drug repurposing of quinine and quinidine has received limited attention. One explanation is the ‘Not Invented Here’ syndrome. The remarkable advances and sophistication in drug discovery and development since the regulatory approval of quinine and quinidine and the renaissance of the drug repurposing strategy since the onset of the coronavirus disease 2019 pandemic call for a comprehensive search for new drug repurposing of quinine and quinidine and their stereoisomers. Furthermore, in addition to chiral switches, applications of other elements of secondary pharmaceuticals to the quinine/quinidine series of stereoisomers should be pursued.

The pharmacological activities of Cinchona quinoline alkaloids were reviewed in 2023. The review listed antimalarial, anticancer, antioxidant, antidiabetic, antifungal, muscle cramp, hair growth stimulant, antimicrobial, antiobesity, antiplatelet, antiviral, anesthetic and antipyretic activities of the four main alkaloids, quinine, quinidine, cinchonidine and cinchonine [101]. The authors concluded that “the pharmacological activity of Cinchona sp is very varied and has the potential to be developed as a drug or cosmetic product.“ An earlier review of the biological activities of Cinchona alkaloids is noted [30]. In 2018, Eyal remarked: “It is hoped that the development of better and safer derivatives of Cinchona alkaloids will extend their therapeutic use” [40]. A recent case in point is the repurposing of Cinchona alkaloids (quinine, quinidine, cinchonidine, cinchonine) as fluorescent logic gates with a receptor₁–fluorophore–spacer–receptor₂ format and photoinduced electron transfer and internal charge transfer mechanisms. The elements of the structures of the Cinchona alkaloids were formatted as follows: the quinoline N atom is receptor₁, 6-methoxyquinoline or quinoline moiety is the fluorophore, the CH(OH)-CH< unit is the spacer and azabicyclic amine is receptor₂ [102].

The plausibility test is not a sufficient condition for the validity of second medical use patent claims. In 2018, the UK Supreme Court held (inter alia) in the Lyrica (pregabalin) landmark judgment that “the proposition that a product is efficacious for the treatment of a given condition must be plausible” [103]. “Plausibility can be demonstrated in the specification without experimental evidence, if there is no substantiated doubt about the theoretical case made for the efficacy of the invention.” For example, “although the specification in the pregabalin patent made it plausible that pregabalin would be effective to treat peripheral neuropathic pain, it did not make it plausible that pregabalin would be effective to treat central neuropathic pain” [12]. The second medical uses of the drug under consideration should be applied to an investigational drug.

Chiral switches of quinine and quinidine to any of their 14 stereoisomers (diastereomers and enantiomers) and their drug repurposing represent an opportunity. Although this drug discovery approach is considered ‘obvious-to-try’ (a patentability criterion for establishing prima facie obviousness) (Table 1) [19,27,104], its actual effects resulting in new medical uses of stereoisomers of quinine and quinidine may turn out to be unexpected. The nonobviousness/inventive step of the patents of such new drugs will then be determined on a case-by-case basis. A case in point is the potential repurposing of the nine epimers of quinine and quinidine [105].

Fixed combination drugs consisting of the natural and unnatural stereoisomers of the quinine/quinidine series and based on the diastereomeric solute–solute interactions of enantiomers [89,97–100] should be explored. Such new drugs will include, inter alia, quasi-racemic and quasi-scalemic mixtures. The antimalarial drug Quinimax, which includes a quasi-scalemic quinine/quinidine component, may serve as a starting point.

The antimalarial activity of the Cinchona alkaloids cinchonidine and cinchonine (Figure 1) was investigated in the 19th century [49]. The drug repurposing strategy may be applied to cinchonidine and cinchonine and their stereoisomers. The Cinchona alkaloid dihydro derivatives 10,11-dihydroquinine, 10,11-dihydroquinidine, 10,11-dihydrocinchonidine and 10,11-dihydrocinchonine [30] and stereoisomers thereof may also be explored accordingly. Following the Nuedexta (dextromethorphan/quinidine) combination drug, other types of chiral switch combinations with the following elements of secondary pharmaceuticals of quinine and quinidine may be considered: polymorphs, salts, ether and ester compositions, dose combinations, prodrugs and metabolites [106].

In 2023, the following definition of drug repurposing was put forward: “Drug repurposing investigates off-patent, approved, and marketed drugs for a novel therapeutic indication” [107]. We submit that drug repurposing may be applied to patented drugs, not only to off-patent drugs. Drug repurposing of quinine and quinidine should not be considered ‘new tricks’.

In spite of the extensive history of the pharmacological and medical activities of quinine and quinidine for almost four centuries, and bearing in mind the rich stereochemistry of these Cinchona alkaloids, quinine and quinidine should be subjected to comprehensive drug repurposing/chiral switch searches for new medical uses. This strategy should also be applied to other chiral drugs containing multiple chirality elements.

Future perspective

Drug repurposing to new medical uses and chiral switches are two elements in the discovery and development of secondary pharmaceuticals. The strategy of drug repurposing peaked during the recent coronavirus disease 2019 pandemic. This trend will hopefully inspire drug repurposing and chiral switches of the diastereomers/quasi-enantiomers quinine and quinidine in the coming 5–10 years. We hope that better and safer derivatives of Cinchona alkaloids will be developed, extending their therapeutic uses [40].

The widened scope of chiral switches includes not only a racemate to single-enantiomer switch, but also other types of switches of the status of chirality. The repurposing of the antiarrhythmic drug quinidine to the antimalarial drug quinine illustrates, post facto (not as a strategy), an application of the drug repurposing/chiral switch combination strategy, a switch of D₁–diastereomer to D₂–diastereomer.

The rich stereochemistry inherent in quinine, quinidine and their 14 stereoisomers opens up the potential exploration from quasi-enantiomers to quasi-racemates (e.g., 1:1 mixture of quinine and quinidine) and to scalemic mixtures (Table 1) of Cinchona alkaloids. Quinidine was withdrawn from the US market in 2019. Nevertheless, a message of this Perspective is, paraphrasing Mark Twain’s 1897 quote: the death of the drugs quinine and quinidine is an exaggeration.

Chiral switch patents have been under attack, describing them by using the negative connotation descriptors ‘evergreening’, ‘product hopping’ and ‘me-too’ and characterizing these patents as ‘obvious-to-try’ (Table 1) [19]. Nevertheless, it is predicted that the application of the chiral switch strategy, alone and in combination with drug repurposing, will continue and will be successful, especially in view of the widened scope.

Cinchona alkaloids (e.g., dihydroquinine) have been shown to exhibit intermolecular diastereomeric solute–solute interactions of enantiomers [89,97–100]. This unusual property should be exploited in the future in the search for new medical uses of mixtures thereof. We call for future research of solute–solute interactions of the stereoisomers of Cinchona alkaloids, including potential combination drugs thereof. The quinine and quinidine stereoisomers, analogs and combinations thereof should serve as new starting points for further drug development.

Executive summary

• Quinine is an essential medicine that changed the world. Quinine and its diastereomeric quasi-enantiomer quinidine have served as prominent chiral resolving agents, chiral catalysts and chiral recognition agents.

• The rich history of the repurposing of the Cinchona alkaloids quinine to quinidine and quinidine to quinine, divided into two periods, the era prior to US drug regulation (1638–1938) and the US drug regulation era (1938–2022), is reviewed.

• The repurposing of quinidine for the treatment of arrhythmia and severe Plasmodium falciparum malaria to its diastereomer quinine for the treatment of uncomplicated P. falciparum malaria is an illustration of the drug repurposing/chiral switch combination strategy.

• The remarkable advances and sophistication in drug discovery and development since the regulatory approval of quinine and quinidine and the renaissance of the drug repurposing strategy since the onset of the coronavirus disease 2019 pandemic call for a comprehensive search for new drug repurposing of quinine and quinidine, including targeting their 14 stereoisomers.

• Chiral switches of quinine and quinidine to any of their 14 stereoisomers (diastereomers and enantiomers) and drug repurposing thereof represent an opportunity for the development of new drugs. Although this drug discovery approach is considered ‘obvious-to-try’ (a patentability criterion for establishing prima facie obviousness), its actual effects resulting in new medical uses of quinine and quinidine stereoisomers may turn out to be unexpected.

• The following pharmacological activities of the four main Cinchona quinoline alkaloids (quinine, quinidine, cinchonidine and cinchonine) were listed in 2023: antimalarial, anticancer, antioxidant, antidiabetic, antifungal, muscle cramps, hair growth stimulant, antimicrobial, antiobesity, antiplatelet, antiviral, anesthesia and antipyretics.

• Fixed combination drugs consisting of the natural and unnatural stereoisomers of the quinine/quinidine series and based on the diastereomeric solute–solute interactions of enantiomers should be explored. Such new drugs will include, inter alia, quasi-racemic and quasi-scalemic mixtures. The antimalarial drug Quinimax, which includes a quasi-scalemic quinine/quinidine component, may serve as a starting point for new drug repurposing/chiral switches.

• Following the Nuedexta (dextromethorphan/quinidine) combination drug, other types of elements of chiral-switch combination with the following elements of secondary pharmaceuticals of quinine and quinidine may be considered: polymorphs, salts, ether and ester compositions, dose combinations, prodrugs and metabolites.

Author contributions

Both authors contributed equally to the manuscript. They conceived the research idea, conducted the research, jointly wrote the manuscript and approved the submitted version.

Acknowledgments

Israel Agranat (IA) is deeply grateful to the illustrious physician Dr Hillel Joffe (1864–1936) for taking great care of his mother, Carmel Friedlaender Agranat (1911–2007), during her pregnancy, curing her of malaria by quinine treatment, thus saving her life and the life of her prematurely born baby (IA).

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None of the authors have any relevant financial and/or non-financial relationships to disclose.

Future Science Group, now Taylor & Francis, disclose that the authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests.

Future Science Group, now Taylor & Francis, disclose that the authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

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