Cu-promoted synthesis of triclosan-Mannich and Glaser adducts: anti-mycobacterial evaluation with in silico validations

Abstract

Aim: The WHO, Global tuberculosis report 2022 estimated number of tuberculosis (TB) cases reached 10.6 million in 2021, reflecting a 4.5% increase compared with the 10.1 million reported in 2020. The incidence rate of TB showed 3.6% rise from 2020 to 2021. Results/methodology: This manuscript discloses Cu-promoted single pot A³-coupling between triclosan (TCS)-based alkyne, formaldehyde and secondary amines to yield TCS-based Mannich adducts. Additionally, the coupling of TCS-alkynes in the presence of Cu(OAc)₂ afforded the corresponding homodimers. Among tested compounds, the most potent one in the series 11 exhibited fourfold higher potency than rifabutin against drug-resistant Mycobacterium abscessus. The selectivity index was also substantially improved, being 26 (day 1) and 15 (day 3), which is four-times better than TCS.

Graphical abstract

Summary points

• The battle against tuberculosis and non-tuberculous mycobacteria (NTM) is becoming a serious challenge due to the emergence of resistance against most effective drugs (isoniazid, rifabutin).

• Cu-promoted Triclosan-Mannich and Glaser adducts have been designed, synthesized and evaluated for their anti-mycobacterial activities against the rough and smooth variant of Mycobacteroides abscessus and Mycobacterium tuberculosis strain.

Results

• The most potent compound of the synthesized series was the Glaser adduct 11 which exhibited good anti-mycobacterial profiles, lower cytotoxicity than triclosan (TCS) checked in THP-1 macrophages and demonstrated a superior selectivity index.

• Docking studies of 11 with InhA_MAB corroborated the observed activities.

Conclusion

• The synthesized Glaser adduct with -NH acetylene linkage between two TCS moieties, in other words, compound 11 proved to be the most potent among the synthesized series, exhibiting MIC₅₀ of 3.125 μg/ml against CIP R strain of M. abscessus. The adduct 11 exhibited equipotent activity compared with TCS and was found to be fourfold more potent than rifabutin. In terms of cytotoxicity, it exhibited lower toxicity toward human THP-1 macrophages than TCS with a selectivity index of 26.01 on CIP R on day 1 and 15.07 on day 3.

Keywords: :

• A³-coupling
• catalase-peroxidase (KatG)
• cu-promoted reaction
• cytotoxicity
• Glaser adducts
• InhA
• in silico studies
• mycolic acid
• non-tuberculous mycobacteria (NTM)
• selectivity index
• triclosan

Financial disclosure

UGC(NFSC) has been acknowledged for providing fellowship to Shekhar (Ref. No. 1758/CSIR-UGC NET JUNE 2019). V Kumar thanks Council of Scientific and Industrial Research (CSIR) for providing financial support (Grant No. 02(0400)/21/EMR-II). We acknowledge the Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation for funding the PhD of MA and the Fondation pour la Recherche Médicale (Equipe FRM EQU202103012588). The authors have no other relevant affiliations or 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 apart from those disclosed.

Competing interests disclosure

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, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

UGC(NFSC) has been acknowledged for providing fellowship to Shekhar (Ref. No. 1758/CSIR-UGC NET JUNE 2019). V Kumar thanks Council of Scientific and Industrial Research (CSIR) for providing financial support (Grant No. 02(0400)/21/EMR-II). We acknowledge the Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation for funding the PhD of MA and the Fondation pour la Recherche Médicale (Equipe FRM EQU202103012588).