Design, synthesis and docking studies of novel anti-HIV agents

Introduction: AIDS therapeutic targets principally consists of three enzymes: reverse transcriptase (RT), protease (PR) and integrase (IN). Integrase strand transfer inhibitors among the HIV inhibitors has the advantage of suitable safety profile and high potency. The chelating motif and coplanar hydrophobic aryl group are the common pharmacophores of an integrase strand transfer inhibitor (INSTI). According to the cyclic chelating group of dolutegravir, we incorporated the chelating group into a cyclic motif and novel 2-mercaptooxazoloxocumarin tricyclic scaffold was designed. Hydrophobic part of the ligand was attached through s-arylation to occupy the same position as the halobenzyl pharmacophoric group of INSTIs. Methods and Results: 4-Hydroxy-3-nitro coumarin was prepared in a nitration procedure of 4-hydroxy coumarin with the aid of concentrated nitric acid and sulfuric acid. Reduction of the 4-hydroxy-3-nitro coumarin in the presence of sodium dithionite and sodium acetate in water gave the 3-amino-4-hydroxy coumarin. 2-Mercaptooxazolocoumarin was prepared by the reaction of carbon disulfide with 3-amino-4-hydroxy coumarin in methanolic potassium hydroxide. Then, this intermediate was treated with substituted benzyl halides in the presence of potassium carbonate and acetone. Final derivatives were recrystallized from ethanol and confirmed by IR, LC-MS (ESI), 1HNMR & 13CNMR. According to the docking results, the tricyclic scaffold could п-stack the 3’-end reactive adenosine in the IN active site just same as the co-crystallized ligand dolutegravir and the ligand heteroatoms complexes the magnesium cofactors in the IN. Conclusions: Here, we introduced a novel scaffold for anti-HIV activity. The superimposed structure with co-crystallized ligand dolutegravir confirmed the potential for integrase inhibitory activity just same as the second generation integrase inhibitor dolutegravir

QSAR Modeling of COX-2 Inhibitory Activity of Thiazinan, Benzthiazinan and Benzdiazinan Derivatives

COX-2 inhibitory activities of some thiazinan, benzdiazinan and benzthiazinan derivatives were modeled by quantitative structure–activity relationship (QSAR) with stepwise-multiple linear regression (SW-MLR) method. The built model was robust and predictive with correlation coefficient (R2) of 0.840 for training and 0.522 for test groups. The quality of the model was evaluated by leave-one out (LOO) cross validation and LOO correlation coefficient (Q2) was 0.639. We also investigated a leverage approach for defining of applicability domain of model. According to QSAR model results, COX-2 inhibitory activity of selected data set had correlation with VE3_Dzm (Logarithmic coefficient sum of the last eigenvector from Barysz matrix weighted by mass), GATS6c (geometrical structure of the considered molecules in a complex way) and GATS5i (Geary autocorrelation of lag 5 weighted by ionization potential) descriptors which derived from their structures

Design, Synthesis and Docking studies of New Quinazolinone Derivatives as Anti-HIV-1 Agents: Quinazolinone Derivatives as Anti-HIV-1 Agents

The Human Immunodeficiency Virus (HIV) infection is a global health challenge that creates an urgent need to develop new therapeutic agents. In this work, a new group of quinazolinone derivatives were designed and synthesized and evaluated their anti-HIV activity. The antiviral assay revealed that some analogues inhibited HIV replication in the cell culture. A docking study using the later crystallographic data available for PFV integrase including its complexes with Mg2+ and dolutegravir, showed that the designed compounds bind into the active site of integrase enzyme such that both carbonyl groups chelate Mg2+ ions. Interestingly, all of the synthesized compounds were found to present no significant cytotoxicity at a concentration of 100 μM. According to the anti-HIV evaluation results, the compound 10f was found as the most active with the inhibition rate of 38%. Therefore, these compounds can provide a very good basis for the development of new anti-HIV agents

Synthesis of Novel 3-(5-(Alkyl/arylthio)-1,3,4-Oxadiazol-2-yl)-8-Phenylquinolin-4(1<i>H</i>)-One Derivatives as Anti-HIV Agents

<p>Novel quinolone derivatives featuring an 1,3,4-oxadiazole ring as a metal-chelating component and a benzyl group base on HIV-1 integrase inhibitors pharmacophore were designed and synthesized. An antiviral assay revealed that most analogues inhibited HIV-1 replication in the cell culture. Our results showed that compounds bearing small alkyl groups as R group were inactive in anti-HIV-1 assay, whereas compounds possessing benzyl or substituted benzyl at the same position showed good anti-HIV activity with the range of 20–57% at 100 μM concentration. Among them, 3-(5-((2-fluorobenzyl)thio)-1,3,4-oxadiazol-2-yl)-8-phenylquinolin-4-(1<i>H</i>)-one (compound <b>13</b>) showed reasonable cell-based antiviral activity (EC₅₀ = 50 μM) with no considerable cytotoxicity (CC₅₀ > 100 μM) in the cell viability assay, suggesting that it may be amenable to further development for identifying new anti-HIV-1 agents. Docking studies using the later crystallographic data available for PFV integrase corroborate favorable binding to the active site of HIV integrase, providing a basis for the design of more potent analogues.</p