Discovery and Pharmacophore Mapping of a Low‐Nanomolar Inhibitor of P. falciparum Growth. (12th November 2019)

• Record Type: Journal Article
• Authors: Bassanini, Ivan; Parapini, Silvia; Galli, Corinna; Vaiana, Nadia; Pancotti, Andrea; Basilico, Nicoletta; Taramelli, Donatella; Romeo, Sergio
• Is Part Of: ChemMedChem. Volume 14:Number 23(2019)
• Page Start: 1982
• Page End: 1994
• Publication Date: 2019-11-12
• Subjects: Plasmodium falciparum -- Antimalarials -- Malaria -- In silico pharmacophore mapping; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900526
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The treatment of malaria, the most common parasitic disease worldwide and the third deadliest infection after HIV and tuberculosis, is currently compromised by the dramatic increase and diffusion of drug resistance among the various species of Plasmodium, especially P. falciparum ( Pf ). In this view, the development of new antiplasmodial agents that are able to act via innovative mechanisms of action, is crucial to ensure efficacious antimalarial treatments. In one of our previous communications, we described a novel class of compounds endowed with high antiplasmodial activity, characterized by a pharmacophore never described before as antiplasmodial and identified by their 4, 4'‐oxybisbenzoyl amide cores. Here, through a detailed structure‐activity relationship (SAR) study, we thoroughly investigated the chemical features of the reported scaffolds and successfully built a novel antiplasmodial agent active on both chloroquine (CQ)‐sensitive and CQ‐resistant Pf strains in the low nanomolar range, without displaying cross‐resistance. Moreover, we conducted an in silico pharmacophore mapping. Abstract : Through an extensive SAR campaign, a new low‐nanomolar inhibitor of P. falciparum growth was discovered. Its in vitro therapeutic index was calculated against healthy human cell lines (HMEC‐1) while its metabolic stability was preliminary investigated and assessed as in vitro microsomal intrinsic clearance in a murine model. Finally, the peculiar structural features of its novel pharmacophore were thoroughly investigated by in silico studies.