Discovery and Pharmacophore Mapping of a Low-Nanomolar Inhibitor of P. falciparum Growth |
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Authors: | Dr. Ivan Bassanini Dr. Silvia Parapini Dr. Corinna Galli Dr. Nadia Vaiana Dr. Andrea Pancotti Prof. Nicoletta Basilico Prof. Donatella Taramelli Prof. Sergio Romeo |
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Affiliation: | 1. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy;2. Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Via Pascal, 36, 20133 Milan, Italy;3. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network;4. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Pascal 36, 20133 Milan, Italy |
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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. |
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Keywords: | Plasmodium falciparum Antimalarials Malaria In silico pharmacophore mapping |
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