Research paper
Design, synthesis and anti-HIV activity of novel quinoxaline derivatives

https://doi.org/10.1016/j.ejmech.2016.04.019Get rights and content

Highlights

  • Integrase enzyme has no cellular equivalent which makes it important target to develop anti-HIV agent.

  • Design of novel anti-HIV agents using 2 ligand based drug design approaches.

  • Designed compound showed crucial interactions in in-silico docking studies.

  • Seven compounds were synthesized and characterized.

  • Compound 7d and 7e showed good anti-HIV activity and are important lead for further modifications.

Abstract

In order to design novel anti-HIV agents, pharmacophore modelling, virtual screening, 3D-QSAR and molecular docking studies were performed. Pharmacophore model was generated using 17 structurally diverse molecules using DISCOtech followed by refinement with GASP module of Sybyl X. The best model containing four features; two donor sites, one acceptor atom and one hydrophobic region; was used as a query for virtual screening in NCI database and 6 compounds with Qfit value ≥98 were retrieved. The quinoxaline ring which is the bio-isostere of pteridine ring, retrieved as a hit in virtual screening, was selected as a core moiety. 3D-QSAR was carried on thirty five 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide derivatives. Contour map analysis of best CoMFA and CoMSIA model suggested incorporation of hydrophobic, bulky and electronegative groups to increase potency of the designed compounds. 50 quinoxaline derivatives with different substitutions were designed on basis of both ligand based drug design approaches and were mapped on the best pharmacophore model. From this, best 32 quinoxaline derivatives were docked onto the active site of integrase enzyme and in-silico ADMET properties were also predicted. From this data, synthesis of top 7 quinoxaline derivatives was carried out and were characterized using Mass, 1H-NMR and 13C-NMR spectroscopy. Purity of compounds were checked using HPLC. These derivatives were evaluated for anti-HIV activity on III-B strain of HIV-1 and cytotoxicity studies were performed on VERO cell line. Two quinoxaline derivatives (7d and 7e) showed good results, which can be further explored to develop novel anti-HIV agents.

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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