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QSAR studies on dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) derivatives, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors

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Author(s): Laxmi Gupta, Asha Patel, Chandrabose Karthikeyan and Piyush Trivedi

Journal: Journal of Current Pharmaceutical Research
ISSN 0976-3171

Volume: 1;
Issue: 1;
Start page: 19;
Date: 2010;
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Keywords: Quantitative Structure–Activity Relationships (QSAR) | Dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) derivatives: Non-nucleoside reverse transcriptase inhibitors: NNRTIs.

ABSTRACT
Objective: Non-nucleoside reverse transcriptase is an essential enzyme required for replication of the acquired immunodeficiency syndrome virus. It is a potent target for anti- HIV therapy. A QSAR study is performed on the series 5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones belonging to dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) derivatives in order to analyze the physicochemical requirements of non-nucleoside reverse transcriptase inhibitors and to provide structural insight into the binding mode of the molecules to the enzyme. This will help in the design of these molecules as non-nucleoside reverse transcriptase inhibitors and predicting the inhibitory activity of the newly designed analogues.Materials & Methods: All the derivatives in the series were sketched using ChemDraw module of ChemOffice 2001 and the sketched structures were subsequently used for the calculation of molecular descriptors available in QSAR software dragon. Empirical, constitutional, topological and functional group descriptors for all molecules were calculated using QSAR software dragon 2005 and correlation between the biological activity and molecular descriptors was found through forward stepwise multiple regression analysis using the method of least squares adopted by statistical program VALSTAT.Results: The generated QSAR models revealed that Hy (hydrophilic factors), MSD (mean square distance index), nCrHR (number of ring quaternary), RBN (total number of rotatable bonds) and ARR (aromatic ratio) descriptors have good correlation to the non-nucleoside reverse transcriptase inhibitors activity.Conclusion: The results obtained by regression analysis indicated that Hy (hydrophilic Factors), which regulates the hydrophilicity of the molecules, is negatively contributing to inhibitory activity thus; enhancement of inhibitory activity can be achieved by substitution with more hydrophobic substituents. Positive contribution of RBN (total number of rotatable bonds) specifies that substitution with groups, which are having rotatable bonds, will impart positive influence on activity. MSD, Mean square distance index (balaban) is contributing negatively to the activity, which suggests that substituents have greater branching will improve inhibitory activity.
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