Design, synthesis and biological evaluation of 2-substituted quinolines as potential antileishmanial agents

Eur J Med Chem. 2013 Nov:69:527-36. doi: 10.1016/j.ejmech.2013.08.028.

Vadiraj S Gopinath ¹, Jakir Pinjari, Ravindra T Dere, Aditya Verma, Preeti Vishwakarma, Rahul Shivahare, Manjunath Moger, Palusa Sanath Kumar Goud, Vikram Ramanathan, Prosenjit Bose, M V S Rao, Suman Gupta, Sunil K Puri, Delphine Launay, Denis Martin

Affiliations

Affiliation

1 Advinus Therapeutics Pvt. Ltd., Bangalore 560 058, India.

PMID: 24095747 DOI: 10.1016/j.ejmech.2013.08.028

Abstract

An analogous library of 2-substituted quinoline compounds was synthesized with the aim to identify a potential drug candidate to treat visceral leishmaniasis. These molecules were tested for their in vitro and in vivo biological activity against Leishmania donovani. Metabolic stability of these compounds was also improved through the introduction of halogen substituents. Compound (26g), found to be the most active; exhibited an IC₅₀ value of 0.2 μM and >180 fold selectivity. The hydrochloride salt of (26g) showed 84.26 ± 4.44 percent inhibition at 50 mg/kg × 5 days (twice daily, oral route) dose in L. donovani/hamster model. The efficacy was well correlated with the PK data observed which indicating that the compound is well distributed.

Keywords

2-Substituted quinolines; Antileishmanial activity; Liver microsomes; Luciferase assay; Metabolic stability.

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