| Autor: |
Rashamuse TJ; Advanced Materials Division, Mintek, Private Bag X3015, Randburg 2194, South Africa.; Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO Wits, Johannesburg 2050, South Africa., Fish MQ; Advanced Materials Division, Mintek, Private Bag X3015, Randburg 2194, South Africa., Coyanis EM; Advanced Materials Division, Mintek, Private Bag X3015, Randburg 2194, South Africa., Bode ML; Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO Wits, Johannesburg 2050, South Africa. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecules (Basel, Switzerland) [Molecules] 2021 Oct 14; Vol. 26 (20). Date of Electronic Publication: 2021 Oct 14. |
| DOI: |
10.3390/molecules26206203 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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