QSAR Study of (5-Nitroheteroaryl-1,3,4-Thiadiazole-2-yl) Piperazinyl Derivatives to Predict New Similar Compounds as Antileishmanial Agents

Abdellah Ousaa,Tahar Lakhlifi,Adnane Aouidate,Samir Chtita,Mounir Ghamali,Mohammed Bouachrine,Bouhya Elidrissi

doi:10.1155/2018/2569129

Abdellah Ousaa, Tahar Lakhlifi + Show 5 more

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https://doi.org/10.1155/2018/2569129

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Abstract

To search for newer and potent antileishmanial drugs, a series of 36 compounds of 5-(5-nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives were subjected to a quantitative structure-activity relationship (QSAR) analysis for studying, interpreting, and predicting activities and designing new compounds using several statistical tools. The multiple linear regression (MLR), nonlinear regression (RNLM), and artificial neural network (ANN) models were developed using 30 molecules having pIC50 ranging from 3.155 to 5.046. The best generated MLR, RNLM, and ANN models show conventional correlation coefficients R of 0.750, 0.782, and 0.967 as well as their leave-one-out cross-validation correlation coefficients RCV of 0.722, 0.744, and 0.720, respectively. The predictive ability of those models was evaluated by the external validation using a test set of 6 molecules with predicted correlation coefficients Rtest of 0.840, 0.850, and 0.802, respectively. The applicability domains of MLR and MNLR transparent models were investigated using William’s plot to detect outliers and outsides compounds. We expect that this study would be of great help in lead optimization for early drug discovery of new similar compounds.

Highlights

Leishmaniasis is a parasitic disease caused by protozoan parasites of the genus Leishmania and is generally recognized as an important public health problem, touching millions of people living mainly in large areas of tropical and subtropical regions
There are only a limited number of drugs that are available for the treatment and control of this Leishmaniasis disease, all of which are associated with limiting factors such as high toxicity, variable efficacy, long dosing schedules, and/or parenteral administration [1, 2]
No vaccine against any clinica form of Leishmaniasis has been commercialized and its treatment relies solely on chemotherapy that has been based on the use of pentavalent antimonial drugs

Summary

Introduction

Leishmaniasis is a parasitic disease caused by protozoan parasites of the genus Leishmania and is generally recognized as an important public health problem, touching millions of people living mainly in large areas of tropical and subtropical regions. There are only a limited number of drugs that are available for the treatment and control of this Leishmaniasis disease, all of which are associated with limiting factors such as high toxicity, variable efficacy, long dosing schedules, and/or parenteral administration [1, 2]. No vaccine against any clinica form of Leishmaniasis has been commercialized and its treatment relies solely on chemotherapy that has been based on the use of pentavalent antimonial drugs. Other drugs, such as pentamidine, miltefosine, and amphotericin B, have been used as alternative medications towards resistant parasites. There is always a need for designing newly potent, safer, and cheaper drugs [3,4,5]

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