ABSTRACT
Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target scaffolds in the AlphaScreenTM HIV-1 IN-LEDGF/p75 inhibition assay identified seventeen compounds exceeding the pre-defined 50% inhibitory threshold at 100 µM concentration. Further evaluation of these compounds in the HIV-1 IN strand transfer assay at 100 µM showed that none of the compounds (with the exception of 10a, 10l, and 11k, with marginal inhibitory percentages) were actively bound to the active site, indicating that they are selectively binding to the LEDGF/p75-binding pocket. In a cell-based HIV-1 antiviral assay, compounds 11a, 11b, 11g, and 11h exhibited moderate antiviral percentage inhibition of 33-45% with cytotoxicity (CC50) values of >200 µM, 158.4 µM, >200 µM, and 50.4 µM, respectively. The antiviral inhibitory activity displayed by 11h was attributed to its toxicity. Upon further validation of their ability to induce multimerization in a Western blot gel assay, compounds 11a, 11b, and 11h appeared to increase higher-order forms of IN.
Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/drug effects , Transcription Factors/antagonists & inhibitors , Catalytic Domain , Cell Line , Computer Simulation , Drug Design , Drug Evaluation, Preclinical , HIV Integrase/chemistry , HIV Integrase/metabolism , HIV Integrase Inhibitors/pharmacology , Host Microbial Interactions/drug effects , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Docking Simulation , Molecular Structure , Protein Multimerization/drug effectsABSTRACT
A facile and efficient one-pot three-component reaction method for the synthesis of thiazine-dicarboxylates is reported. Reaction of an isocyanide and dialkyl acetylenedicarboxylate with 2-amino-4H-1,3-thiazin-4-one derivatives containing both an acidic proton and an internal nucleophile gave the products in good yields of 76-85%. The reactivity of dialkyl acetylenedicarboxylates was further tested in the synthesis of thiazole-pyrimidines where a two-component reaction of 2-aminothiazole with dialkyl acetylenedicarboxylates was successfully converted to a more efficient three-component reaction of a thiourea, α-haloketone and dialkyl acetylenedicarboxylate (DMAD/DEtAD) to give thiazole-pyrimidines in good yields of 70-91%.
ABSTRACT
An HIV-1 subtype C specific assay was established for integrase genotyping from 51 integrase inhibitor-naive patient plasma samples and 22 antiretroviral drug-naive primary viral isolates from South Africa. Seventy-one of the 73 samples were classified as HIV-1 subtype C and two samples were unique AC and CG recombinants in integrase. Amino acid sequence analysis revealed there were no primary mutations (Y143R/C/H, Q148H/R/K, and N155H/S) associated with reduced susceptibility to the integrase inhibitors raltegravir and elvitegravir. However, one sample had the T97A mutation, three samples had the E157Q and V165I mutations, and the majority of samples contained the polymorphic mutation V72I. The expected finding of no major integrase mutations conferring resistance to integrase inhibitors suggests that this new antiretroviral drug class will be effective in our region where HIV-1 subtype C predominates. However, the impact of E157Q and other naturally occurring polymorphisms warrants further phenotypic investigation.
