ArticlePathogens and disease2017
Design, synthesis and antiviral evaluation of novel heteroarylcarbothioamide derivatives as dual inhibitors of HIV-1 reverse transcriptase-associated RNase H and RDDP functions.
Article in Pathogens and disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 34 citations in OpenAlex.
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- Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Carbonic Anhydrase Inhibition with Sulfonamides Incorporating Pyrazole- and Pyridazinecarboxamide Moieties Provides Examples of Isoform-Selective Inhibitors.Molecules (Basel, Switzerland) · 2021Article
- In Vitro Anti-HIV-1 Reverse Transcriptase and Integrase Properties ofPlants (Basel, Switzerland) · 2021Article
- Pyrroles as Privileged Scaffolds in the Search for New Potential HIV Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Synthesis of Antimicrobial Benzimidazole-Pyrazole Compounds and Their Biological Activities.Antibiotics (Basel, Switzerland) · 2021Review
- Selected βMolecules (Basel, Switzerland) · 2021Review
- Bioactive pyrrole-based compounds with target selectivity.European journal of medicinal chemistry · 2020Review
- 2-(Arylamino)-6-(trifluoromethyl)nicotinic Acid Derivatives: New HIV-1 RT Dual Inhibitors Active on Viral Replication.Molecules (Basel, Switzerland) · 2020Article
- From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2019Article
- New targets for HIV drug discovery.Drug discovery today · 2019Review
- Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
In the continuous effort to identify new HIV-1 inhibitors endowed with innovative mechanisms, the dual inhibition of different viral functions would provide a significant advantage against drug-resistant variants. The HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) is the only viral-encoded enzymatic activity that still lacks an efficient inhibitor. We synthesized a library of 3,5-diamino-N-aryl-1H-pyrazole-4-carbothioamide and 4-amino-5-benzoyl-N-phenyl-2-(substituted-amino)-1H-pyrrole-3-carbothioamide derivatives and tested them against RNase H activity. We identified the pyrazolecarbothioamide derivative A15, able to inhibit viral replication and both RNase H and RNA-dependent DNA polymerase (RDDP) RT-associated activities in the low micromolar range. Docking simulations hypothesized its binding to two RT pockets. Site-directed mutagenesis experiments showed that, with respect to wt RT, V108A substitution strongly reduced A15 IC50 values (12.6-fold for RNase H inhibition and 4.7-fold for RDDP), while substitution A502F caused a 9.0-fold increase in its IC50 value for RNase H, not affecting the RDDP inhibition, reinforcing the hypothesis of a dual-site inhibition. Moreover, A15 retained good inhibition potency against three non-nucleoside RT inhibitor (NNRTI)-resistant enzymes, confirming a mode of action unrelated to NNRTIs and suggesting its potential as a lead compound for development of new HIV-1 RT dual inhibitors active against drug-resistant viruses.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.