Design, Synthesis And Bioactivity Evaluation Of Novel Substitutde 1, 2, 4-Triazole Derivatives As HIV-1 NNRTIs

Nowadays almost every stage of life period and related enzymes of HIV have become pharmacal target for anti-HIV drug design.The reverse transcriptase(RT) Plays a crucial role in the replication of HIV-1 life cycle,and is responsible for the conversion of the single stranded RNA viral genome into double-stranded DNA that subsequently integrates into the host DNA.Because of the distinct function of RT in the virus life cycle,it is one of the important targets of antiviral therapy.Two main classes of RT inhibitors have been hitherto discovered:(1) nucleoside reverse transcriptase inhibitors(NRTIs),which compete with natural substrates by mimicking the normal deoxynucleoside triPhosPhate and function as hainterminators,and(2) the non-nucleosidereverse transeriptase inhibitors(NNRTIs),which inhibit the enzylne by an non-competitively allosteric mechanism involving binding to a site adjacent to the deoxyribonucleoside triphosPhate binding site o the enzyme.Both of them have been found to be efective in halting the enzymatic function of RT.In this paper,on the basis of the general crystal structure of the HIV-1 RT complexed with NNRTIs,and accord to the general principle of bioisosteric replacement which is a strategy of medicinal chemistry for the rational design of new drugs applied with a lead compound as a special process of molecular modification, we screened 4-arylideneamino-5-alkylthio derivative of 4-amino-3-(2'-furyl)-5-mercapto-4H- 1,2,4-triazole 4e,a new class of specific NNRTI,as lead compound. Furthermore consulted to the structure-activity relationship(SAR) and crystal structure of 4-benzyl-3-thienyl-5-mercapto-4H-1,2,4-triazole derivatives,we designed 2 series 4-amino-3-(4'-pyridine)-5-mercapto- 4H-1,2,4-triazole derivatives: 3-(benzylthio)-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-amine series and 4-(benzylidene amino)-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol series.For the preparation of the newly designed molecules,target compounds were from an one-pot reaction to prepare 4-amino-3-(pyridin-4-yl) -5-mercapto-1,2,4-triazole,which came from the reaction of pyridin-4-yl acid hydrazide with excess hydrazine,then the triazole core was synthesized by condensation with aromatic aldehydes to afford Schiff's bases or alkylation with benzyl halides.The chemical structures of these compounds are identified by IR,MS, and 1H-NMR spectra.The preliminary activity and cytotoxicity screening of the newly designed and synthesized compounds were tested in MT-4 cells for inhibition of HIV-1.The screening results indicate that some compounds exhibit inhibition activity of HIV-1. Among the evaluated compounds,compound 2a emerges as the most active HIV-1 inhibitor with EC₅₀=1.08μM and CC₅₀=58.2μM,SI=54,which provides useful information for further investigation of 1,2,4-triazole based NNRTIs.