title: GRIND2-based 3D-QSAR and prediction of activity spectra for symmetrical bis-pyridinium salts with promastigote antileishmanial activity.
abstract: Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes. These compounds are considered structural analogues of pentamidine, where the amidino moiety, protonated at physiological pH, is replaced by a positively charged nitrogen atom as a pyridinium ring. In this work, a statistically significant GRIND2-based 3D-QSAR model was built and biological activity predictions were in silico carried out allowing rationalization of the different activities recently obtained against Leishmania donovani (in L. donovani promastigotes) for a data set of 19 bis-pyridinium compounds. We will emphasize the most important structural requirements to improve the biological activity and probable interactions with the biological receptor as a guide for lead and prototype optimization. In addition, since no information about the actual biological target for this series of active compounds is provided, we have used Prediction of Activity Spectra for Biologically Active Substances to propose our compounds as potential nicotinic α6β3β4α5 receptor antagonists. This proposal is reinforced by the high structural similarity observed between our compounds and several anthelmintic drugs in current clinical use, which have the same drug action mechanism here predicted. Such new findings would be confirmed with further and additional experimental assays.
authors: a Faculdade de Ciências Farmacêuticas de Ribeirão Preto , USP , Av. do Café S/N, CEP: 14040-903, Ribeirão Preto , SP , Brazil.
authors: Evelyn Mirella Lopes Pina
authors: EMLP
authors: Diniz
authors: a Faculdade de Ciências Farmacêuticas de Ribeirão Preto , USP , Av. do Café S/N, CEP: 14040-903, Ribeirão Preto , SP , Brazil.
authors: Carlos Henrique
authors: CH
authors: Tomich de Paula da Silva
authors: b Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , c/ Campus de Cartuja s/n, Granada 18071 , Spain.
authors: Verónica
authors: V
authors: Gómez-Perez
authors: a Faculdade de Ciências Farmacêuticas de Ribeirão Preto , USP , Av. do Café S/N, CEP: 14040-903, Ribeirão Preto , SP , Brazil.|b Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , c/ Campus de Cartuja s/n, Granada 18071 , Spain.
authors: Leonardo Bruno
authors: LB
authors: Federico
authors: b Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , c/ Campus de Cartuja s/n, Granada 18071 , Spain.
authors: Joaquín María
authors: JM
authors: Campos Rosa
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000469:parasitology; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D011726:Pyridinium Compounds
keywords: 3D-QSAR; GRIND2; Leishmania donovani; PASS; antileishmanial activity; bis-pyridinium; cyclophanes