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Discovery and Pharmacophore Mapping of a Low‐Nanomolar Inhibitor of P. falciparum Growth
Author(s) -
Bassanini Ivan,
Parapini Silvia,
Galli Corinna,
Vaiadia,
Pancotti Andrea,
Basilico Nicoletta,
Taramelli Donatella,
Romeo Sergio
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900526
Subject(s) - pharmacophore , plasmodium falciparum , malaria , in silico , antimalarial agent , drug resistance , drug , computational biology , drug discovery , pharmacology , combinatorial chemistry , biology , chemistry , stereochemistry , bioinformatics , immunology , biochemistry , microbiology and biotechnology , gene
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.