Exploring clotrimazole-based pharmacophore: 3D-QSAR studies and synthesis of novel antiplasmodial agents

Simone Brogi; Margherita Brindisi; Bhupendra P Joshi; Salvatore Sanna Coccone; Silvia Parapini; Nicoletta Basilico; Ettore Novellino; Giuseppe Campiani; Sandra Gemma; Stefania Butini

doi:10.1016/j.bmcl.2015.09.007

Exploring clotrimazole-based pharmacophore: 3D-QSAR studies and synthesis of novel antiplasmodial agents

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5412-8. doi: 10.1016/j.bmcl.2015.09.007. Epub 2015 Sep 5.

Affiliations

¹ European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy.
² European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.
³ European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Via Pascal 36, 20133 Milan, Italy.
⁴ European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy; Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università di Milano, Via Pascal, 36, 20133 Milan, Italy.
⁵ European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Farmacia, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
⁶ European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy. Electronic address: [email protected].
⁷ European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy. Electronic address: [email protected].

PMID: 26428874
DOI: 10.1016/j.bmcl.2015.09.007

Abstract

We report herein the generation and validation of a 3D-QSAR model based on a set of antimalarials previously described by us and characterized by a clotrimazole-based pharmacophore. A novel series of derivatives was synthesized and showed activity against Plasmodium falciparum chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) strains. Gratifyingly, compounds 35a-c showed interesting activity against P. falciparum CQ-R strains with improved predicted physico-chemical properties.

Keywords: 3D-QSAR; Clotrimazole; Ligand-based; Malaria; Plasmodium falciparum.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemistry*
Antimalarials / pharmacology
Clotrimazole / chemistry
Clotrimazole / pharmacology*
Drug Design*
Ligands
Plasmodium falciparum / drug effects*
Quantitative Structure-Activity Relationship

Substances

Antimalarials
Ligands
Clotrimazole