Design, Synthesis, Docking Studies, and Biological Evaluation of Novel 2-Hydroxyacetophenone Derivatives as Anti-HIV-1 Agents.

BACKGROUND: The persistence of HIV mutations and the existence of multidrug resistance have produced an opportunity for an array of innovative anti-HIV medicines with a variety of structures that target HIV key enzymes. OBJECTIVE: The goal of this work was to find a new class of anti-HIV drugs founded on HIV integrase inhibitor pharmacophores. METHODS: A novel class of 2-hydroxy acetophenone analogs featuring substituted benzamide or N-phenylthiourea groups was designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors (INs). RESULTS: Most of the synthesized analogs were found to be moderately active against the virus, with EC50 values ranging from 40 to 140 µM. Additionally, it was found that most of the compounds presented no considerable cytotoxicity (CC50 > 500 µΜ). The most potent compounds substituting with 4-fluorobenzamide (compound 7) and 4-methylbenzamide (compound 9) rings inhibited the HIV-1 replication by EC50 values of 40 and 45 µΜ, respectively. Docking studies using the crystallographic data available for PFV IN indicated that the Mg2+ coordination might be the possible mechanism of the anti-viral activity. CONCLUSION: Our findings proved that the synthesized analogs may suggest a very good basis for the development of new anti-HIV-1 agents.

Novel Benzoxazin-3-one Derivatives: Design, Synthesis, Molecular Modeling, Anti-HIV-1 and Integrase Inhibitory Assay.

INTRODUCTION: Integrase is a validated drug target for anti-HIV-1 therapy. The second generation integrase inhibitors display π-stacking interaction ability with 3'-end nucleotide as a streamlined metal chelating pharmacophore. METHODS: In this study, we introduced benzoxazin-3-one scaffold for integrase inhibitory potential as bioisostere replacement strategy of 2-benzoxazolinone. RESULTS: Molecular modeling studies revealed that amide functionality alongside oxadiazole heteroatoms and sulfur in the second position of oxadiazole ring could mimic the metal chelating pharmacophore. The halobenzyl ring occupies hydrophobic site created by the cytidylate nucleotide (DC-16). CONCLUSION: The most potent and selective compound displayed 110 µM IC50 with a selectivity index of more than 2.

Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives.

BACKGROUND: The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle. OBJECTIVE: Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV. METHODS: Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-component reaction from 3-amino-4-hydroxycoumarin, isatoic anhydride and benzaldehyde derivatives. RESULTS: In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well. CONCLUSION: Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.

Molecular Docking and QSAR Study of 2-Benzoxazolinone, Quinazoline and Diazocoumarin Derivatives as Anti-HIV-1 Agents.

A series of 2-benzoxazolinone, diazocoumarin and quinazoline derivatives have been shown to inhibit HIV replication in cell culture. To understand the pharmacophore properties of selected molecules and design new anti-HIV agents, quantitative structure-activity relationship (QSAR) study was developed using a descriptor selection approach based on the stepwise method. Multiple linear regression method was applied to relate the anti-HIV activities of dataset molecules to the selected descriptors. Obtained QSAR model was statistically significant with correlation coefficient R2 of 0.84 and leave one out coefficient Q2 of 0.73. The model was validated by test set molecules giving satisfactory prediction value (R2 test) of 0.79. Molecules also were docked on HIV integrase enzyme and showed important interactions with the key residues in enzyme active site. These data might be helpful for design and discovery of novel anti-HIV compounds.

Design, Synthesis, Molecular Modeling, In Silico ADME Studies and Anti-HIV-1 Assay of New Diazocoumarin Derivatives.

Some new diazo incorporated coumarin compounds were designed and synthesized to evaluate their anti-HIV activity. Overall, compounds were active against HIV at 100 µM. Additionally, no cytotoxic effect was observed at this concentration. The compound with 4-chlorobenzyl group indicated the best anti-HIV activity (52%). Docking studies using the later crystallographic data available for PFV integrase showed similar binding modes to HIV-1 integrase inhibitors. On the basis of these data, nitrogen atoms of 1,3,4-oxadiazole ring have been involved in the Mg2+ chelation and 4-chlorobenzyl group occupies the same position as 4-flourobenzyl group of raltegravir in the active site. In addition, in silico ADME assay demonstrated favorable physicochemical properties for the new designed compounds. Thus, synthesized structures could be introduced as a novel template for designing safe anti-HIV compounds with integrase inhibitory potential.