Quinoline carboxamide core moiety-based compounds inhibit P. falciparumfalcipain-2: Design, synthesis and antimalarial efficacy studies

• Published in: Bioorganic chemistry 2021-03, Vol.108, p.104514-104514, Article 104514
• Main Authors: Singh, Anju, Kalamuddin, Md, Maqbool, Mudasir, Mohmmed, Asif, Malhotra, Pawan, Hoda, Nasimul
• Format: Article
• Language: English
• Subjects: Drug development; Falcipain-2 (FP2); Malaria; P. falciparum; Quinoline carboxamide
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104514

[Display omitted] •A set of 25 quinoline carboxamide-based compounds was designed and synthesized to inhibit P. falciparum FP2.•Integration of molecular hybridization strategy with in silico drug design was adopted.•Compounds Qs17, Qs18, Qs20 and Qs21 displayed best results in docking and in vitro FP2 inhibition.•These compounds inhibited P. falciparum growth with IC50 values: 1.05, 1.95, 1.43 and 0.81 µM, respectively.•Morphological and food-vacuole abnormalities much better than E-64 were observed. Targeting Falcipain-2 (FP2) for the development of antimalarials is a promising and established concept in antimalarial drug discovery and development. FP2, a member of papain-family cysteine protease of the malaria parasite Plasmodium falciparum holds an important role in hemoglobin degradation pathway. A new series of quinoline carboxamide-based compounds was designed, synthesized and evaluated for antimalarial activity. We integrated molecular hybridization strategy with in-silico drug design to develop FP2 inhibitors. In-vitro results of FP2 inhibition by Qs17, Qs18, Qs20 and Qs21 were found to be in low micromolar range with IC50 4.78, 7.37, 2.14 and 2.64 µM, respectively. Among the 25 synthesized compounds, four compounds showed significant antimalarial activities. These compounds also depicted morphological and food-vacuole abnormalities much better than that of E-64, an established FP2 inhibitor. Overall these aromatic substituted quinoline carboxamides can serve as promising leads for the development of novel antimalarial agents.