Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors

• Published in: Arabian journal of chemistry 2019-11, Vol.12 (7), p.1436-1446
• Main Authors: Mahesh, Radhakrishnan, Mundra, Sourabh, Devadoss, Thangaraj, Kotra, Lakshmi P.
• Format: Article
• Language: English
• Subjects: Antimalarial agents; Ligand-based drug design; Malaria; Plasmodium falciparum; Structure–activity relationships (SARs)
• ISSN: 1878-5352; 1878-5379
• DOI: 10.1016/j.arabjc.2014.11.008

The cysteine protease, falcipain-2 is an important drug target in human malaria parasite Plasmodium falciparum. A new series of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives 5(a–t) were designed as per pharmacophoric requirements of falcipain-2 inhibitors using ligand-based approach. The target compounds were synthesized from the key intermediate, 2-(1,4-Diazepan-1-yl)-N-phenylacetamide, by coupling it with appropriate carboxylic acids using carbodiimide chemistry. Structural features of target compounds were characterized by spectral data (1H NMR, and mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Five compounds 5b, 5g, 5h, 5j, 5k showed good inhibitory activity (>60%), against falcipain-2 at 10μM concentration, and fifteen compounds showed weak to moderate inhibitor activity. Compound 5g, the most potent compound from this series showed 72% inhibition at 10μM concentrations.