Research paperDesign, synthesis and anti-HIV activity of novel quinoxaline derivatives
Graphical abstract
Introduction
Acquired immune-deficiency syndrome (AIDS) is a fatal condition developed due to infection of human immunodeficiency virus (HIV). The infection with HIV virus weakens body's defense system and hence, person becomes susceptible to various infections [1]. Integrase enzyme, unique to the human immunodeficiency virus (HIV), lacks its equivalent in the human body. The adverse effects like rash and neuropsychiatric disorders associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) and cardio toxicity associated with protease inhibitors are of major concerns of current drug therapy. Thereby, replacement with integrase inhibitors which are expected to have least side effects in drug regime, can be beneficial [2], [3]. Drug resistance due to development of resistance virus is another major drawback of available anti-HIV drugs. The combination of other anti-HIV drugs with integrase inhibitors has shown prominent effects on drug resistant virus [4]. HIV integrase with high therapeutic index is a rational target for treating HIV infection and preventing AIDS. Raltegravir [5], Elvitegravir and Dolutegravir are three integrase inhibitors available in market. Dolutegravir came into the market in 2013 and no resistance has been reported till date. Resistance to Raltegravir and Elvitegravir is already reported, but no side effects are noted [6], [7]. Hence, there is a urgent need to develop more efficient anti-HIV agents.
To design novel anti-HIV agents, two ligand based drug design approaches viz. pharmacophore modelling and 3D-QSAR were used. The results of both methods were combined to design novel quinoxaline derivatives, followed by synthesis and characterization. These derivatives were further evaluated for anti-HIV and cytotoxicity studies.
Section snippets
Pharmacophore model generation and validation
Ligand based pharmacophore model was generated to gain information about necessary features to be considered for designing of anti-HIV agents. All seventeen inhibitors of training set (Structures and IC50 values of all molecules are given in Table 1) were aligned using DISCOtech module of Sybyl X; molecular modelling software by Tripos Inc., St. Louis, MO. Top five generated pharmacophore models along with their size, hits, score, tolerance and Dmean are shown in Table 2. The model 36 with
Conclusion
With the aim to find novel HIV inhibitors, two ligand based drug design approaches: pharmacophore modelling and 3D-QSAR study were used initially. The information obtained through both approaches in form of features of pharmacophore model, hits of virtual screening and 3D-QSAR contour maps were used to design novel anti-HIV agents. Designed compounds were then docked into the active site of HIV-1 integrase enzyme and few best docked compounds were selected for synthesis on the basis of their
Dataset preparation for pharmacophore modelling
Seventeen previously reported HIV-1 integrase inhibitors from different chemical classes were selected for training set with IC50 value ranging from 0.001 to 76 μM (Table 5). SKETCH function of Sybyl X was used to sketch selected inhibitors. Partial atomic charges were calculated by Gasteiger Huckel method and energy minimization was performed using Tripos force field. Distance tolerance was set 0.05–1.0 nm and feature requirement was set at 3–7.
Pharmacophore model generation
DISCOtech module of Sybyl X was used to align
Acknowledgement
The Authors SP, BP and HB are thankful to Nirma University, Ahmedabad, India for providing necessary facilities and support to carry out the research work.
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