Maheshkumar R Borkar

SVKM’S Dr. Bhanuben Nanavati College of Pharmacy, India

Title: Novel Pyridone Scaffolds Against Neglected Tropical Disease Leishmaniasis: Synthesis, Biological Evaluation, Cytotoxicity, Pharmacokinetic and In Silico Study

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Biography

Currently working as Assistant Professor Dept. of Pharmaceutical Chemistry SVKM’S Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India. Thrust research areas include Synthesis of NCEs, Molecular Modeling, Computer Aided Drug Design, QSAR. Design, synthesis and evaluation of novel chemical entities (NCEs) against various infectious diseases like TB, Leishmania, Fungal, Bacterial etc. Also, working on novel QSAR methodologies, like HomoSAR (Peptide QSAR), CoRIA, eCORIA etc.

Abstract

Introduction: Leishmaniasis is one of the important neglected tropical diseases caused by protozoan parasites belonging to the genus Leishmania. Currently available drugs for treatment of this disease are associated with severe complications such as toxicity, drug resistance, and cost. Despite being WHO's research priority, the optimum treatment for this disease has not been found yet. In order to overcome these problems, efforts have been made to search for new and more effective leishmanicidal drugs.

Methods: In the present work 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives were synthesized by reacting 4-hydroxy-6-methyl-2H-pyran-2-one with different amines and followed by reaction with substituted phenyl isocyanates. All the derivatives were screened for their antileishmanial activity. Cytotoxicity and metabolic study were performed for most active compounds. Finally, in silico study was carried out to identify the potential biological targets and gain an insight into the ligand–receptor interactions for bioactive molecules.

Results: Six compounds in this series demonstrate a dose-dependent killing of the promastigotes. Their IC50 values range from 55 to 77 ?g/mL. Pharmacokinetic studies on rat liver microsomes show that these compounds are metabolically stable. Also, the molecules are highly specific against leishmania as evidenced by their weak antibacterial and antifungal activity. In-vitro cytotoxicity study show the compounds are devoid of cytotoxicity. Molecular modelling studies reveals that these molecules show good binding affinity towards Leishmania donovani topoisomerase 1 (LdTop1).

Conclusion: The study shows that 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives have the potential to be developed as promising leads against leishmaniasis.