DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL QUINOLINE ANALOGUES AS HIV-1 INTEGRASE INHIBITOR

摘要

A progression of fourteen narrative quinolonyl diketo acid analogs were planned, synthesized, identified by IR, NMR, CHN and MS supernatural analysis and evaluated as potential HIV-1 Integrase hinders. Compounds of Zinc database were surfed considering Elvitegravir as standard. Nearly 99 compounds were identified and docked in the active site of HIV-1 integrase. Molecular docking study of compounds 1, 4 and 7 showed docking score -10.38, -9.31 and -10.12 respectively as that of set drug Elvitegravir -4.93. The docking poses to open the interaction of the ligands with preferred amino acids. The standard drug Elvitegravir displayed connections with lys156, Asn155, Lys159 and Thr66. Raltegravir showed hydrogen bonding with Asp 116. A round fourteen target diketoquinolines were chosen for advance synthesis with the help of substituted oxoquinoline-3-carboxylate as starting material. In-vitro biological evaluation open that some of the upper-class compounds exhibited moderate to good inhibitory activity besides HIV1 Integrase compared to the reference drugs Raltegravir and Nevirapine. Compounds 1, 2, 3 and 4 weakly inhibited HIV-1 integrase at EC50 of 0.31, 0.25, 0.22 & 0.21 with the therapeutic index 242, 260, 266 and 278 respectively. The cytotoxicity of upper-class compounds on C8166 cells was very low, the CC50 value was higher than 200 μM, except for few compounds. As an optimistic control drug, Nevirapine showed significant anti-HIV-1 activity (ECsub50 /sub= 0.015~0.016 μM) in-vitro, and the CCsub50/sub was higher than 200 μM, with a therapeutic index value of 12418.50. Compound 14 exhibited significant inhibition of HIV-1 syncytium and integrase at ECsub50/sub 0.25 and 0.12 respectively.