Synthesis, Biological Activity, and Crystal Structure of Potent Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase That Retain Activity against Mutant Forms of the Enzyme † (original) (raw)
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Bioorganic & Medicinal Chemistry, 2010
A series of novel benzimidazolones and their analogues, characterized by the presence of one or more methyl groups or other bioisosteric moieties at different positions of the phenyl ring at N-1, were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the new compounds proved to be highly effective in inhibiting both HIV-1 replication in MT4 cells with minimal cytotoxicity and RT enzyme at nanomolar concentrations. Some derivatives were also tested against RTs containing single amino acid mutations responsible for resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs). The different potencies displayed by the new compounds were studied using molecular modeling. (A.-M. Monforte).
Journal of The Chilean Chemical Society, 2007
A novel approach to the development of a new class of HIV-1 RT inhibitors is reported. The 1-benzoyl-2-aryl-1H-benzimidazole series was designed as a combination of two previously reported active scaffolds, the benzimidazole and benzoyl moieties. The active compounds of the series effectively blocked the reverse transcription in the micromolar range in an in vitro assay containing the wild-type enzyme. We have demonstrated that the 2-nitrophenyl C-2 substituent is an important structural feature for the desired biological activity in this series. Molecular docking experiments suggest that the active compounds adopt a butterflylike conformation within the binding pocket of the enzyme, with the benzoyl moiety located in an extended hydrophobic region defined mainly by Tyr181, Tyr188, and Trp229.
Journal of the Chilean Chemical Society, 2007
A novel approach to the development of a new class of HIV-1 RT inhibitors is reported. The 1-benzoyl-2-aryl-1H-benzimidazole series was designed as a combination of two previously reported active scaffolds, the benzimidazole and benzoyl moieties. The active compounds of the series effectively blocked the reverse transcription in the micromolar range in an in vitro assay containing the wild-type enzyme. We have demonstrated that the 2-nitrophenyl C-2 substituent is an important structural feature for the desired biological activity in this series. Molecular docking experiments suggest that the active compounds adopt a butterfly-like conformation within the binding pocket of the enzyme, with the benzoyl moiety located in an extended hydrophobic region defined mainly by Tyr181, Tyr188, and Trp229.
Synthesis and HIV1 inhibition of novel benzimidazole derivatives
Bioorganic & Medicinal Chemistry Letters, 1995
A range of novel benzimidazole derivatives, some bearing analogy to TIBO, have been synthesized, and evaluated for inhibition of HIV-1 infectivity. The most active and selective compounds are a series of N-alkoxy-2-alkylbenzimidazoles, several having EC50 < 10~M (one sub-micromolar at 600nM), and selectivity ratios of 10-167. The most selective benzimidazoles, 18a, 18c, show modest RT inhibition, and binding assays indicate gp120-binding is not a target.
Journal of Medicinal Chemistry, 2011
This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, S RN 1) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 24 showed a significant EC 50 value close to 6.4 nM against HIV-1 IIIB, a moderate EC 50 value close to 54 μM against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC 50 > 100 μM).
Journal of Medicinal Chemistry, 2008
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.
Bioorganic & Medicinal Chemistry, 2011
A series of (±)-benzhydrol derivatives featuring the essential sulfonamide group at the para position on the C-ring were synthesized and evaluated for the potential anti-HIV activity in C8166 cells. Most of these analogues demonstrated low concentration inhibitory activity with EC 50 values less than 1 lM against the wild-type HIV-1. In particular, compound 7h was identified as the highest active inhibitor of wildtype HIV-1 with an EC 50 value of 0.12 lM and selectivity index value of 312.73. Furthermore, some of them also exhibited moderate activity against the double mutant strain A 17 (K103N + Y181C) with EC 50 values lower than 5 lM. In addition, the binding modes with RT and the preliminary structureactivity relationships of these derivatives were also explored for further chemical modifications.
Chemical Biology & Drug Design, 2008
We have performed the docking of sulfonyl hydrazides complexed with cytosolic branched-chain amino acid aminotransferase (BCATc) to study the orientations and preferred active conformations of these inhibitors. The study was conducted on a selected set of 20 compounds with variation in structure and activity. In addition, the predicted inhibitor concentration (IC 50 ) of the sulfonyl hydrazides as BCAT inhibitors were obtained by a quantitative structure-activity relationship (QSAR) method using three-dimensional (3D) vectors. We found that three-dimensional molecule representation of structures based on electron diffraction (3D-MoRSE) scheme contains the most relevant information related to the studied activity. The statistical parameters [cross-validate correlation coefficient (Q 2 = 0.796) and fitted correlation coefficient (R 2 = 0.899)] validated the quality of the 3D-MoRSE predictive model for 16 compounds. Additionally, this model adequately predicted four compounds that were not included in the training set.
Antimicrobial Agents and Chemotherapy, 1995
To identify the minimal structural elements necessary for biological activity, the rigid tricyclic nucleus of the known human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor tetrahydroimidazobenzodiazepinthione was subjected to systematic bond disconnection to obtain simpler structures. A rational selection and testing of modeled analogs containing these potential pharmacophoric moieties led to the discovery of a new series of nonnucleoside inhibitors of RT.