Design And Synthesis Of Triazole Derivatives As HIV-1Integrase Inhibitors

The design and synthesis of HIV-1integrase inhibitors have always been one ofthe hot topics. It has been found that diverse kinds of compounds process bioactivityagainst HIV-1integrase, among which the aryl β-diketo acid derivatives are the onlyinhibitors of HIV-1integrase approved by FDA and also the type of inhibitors whoseHIV-1integrase inhibitory mechanism is known so far. On the other hand, the5-chloro-2-hydroxy-3-(1H-1,2,3-triazol-1-yl)benzoic acids synthesized in our labpreviously are observed to have good activity of anti-integrase. On the basic of theobservation, herein using5-chloro-2-hydroxy-3-(1H-1,2,3-triazol-1-yl)benzoic acidsas lead compound, we reported its structural modification, synthesis and evaluation ofHIV-1integrase inhibitory activity as follows:1. For N-hydroxy-1H-1,2,3-triazole-4-carboxamide derivativeswe designed the novel targets products N-hydroxy-1-phenyl-1H-1,2,3-triazole-4-carboxamides and1-benzyl-N-hydroxy-1H-1,2,3-triazole-4-carboxamides by meansof making the salicylic acid ring of5-chloro-2-hydroxy-3-(1H-1,2,3-triazol-1-yl)benzoic acid open and further optimizing the pharmacophore to be N-hydroxycarboxamide combining N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide whichhave been reported with good potency for anti-integrase of HIV-1. Then due to―clickreaction‖having the advantages that are fast, economic and green, we applyed it toobtain14target products N-hydroxy-1H-1,2,3-triazole-4-carboxamide derivativessmoothly through N-hydroxypropiolamide reacting with azidobenzene and(azidomethyl)benzene respectively. In addition, all of the products were identified by1H NMR,13C NMR, IR and MS.2. For1,2,3-triazolo[4,5-b]pyridine carboxylic acid derivativesIn consideration of the issue that the single bond may rotate to cause theunfavorable conformation in N-hydroxy-1H-1,2,3-triazole-4-carboxamide derivatives,we optimized the structure of salicylic acid ring to be dihydropyridone carboxylic acidcombining the characteristics of pharmacophore for the inhibitors of HIV-1integraseElvitegravir, then designing a series of novel1,2,3-triazolo[4,5-b]pyridine carboxylicacids through making the triazole ring and the pyridine ring together. And the15target products were prepared after9steps reactions. In addition, all of theintermediates were confirmed by1H NMR and/or13C NMR and the target products were identified by1H NMR,13C NMR, IR and MS.Finally, we tested the antiviral bioactivity in vitro for the29target products bythe method of MAGI, and the results exhibit that all of the products have poorbioactivity.