Two targeted sets of novel 1,5-diaryl-1
H-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
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Two targeted sets of novel 1,5-diaryl-1
H-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 AlphaScreen
TM 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 (CC
50) 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.
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