Synthesis, Biological Activity, and ADME Properties of Novel <i>S</i>‐DABOs/<i>N</i>‐DABOs as HIV Reverse Transcriptase Inhibitors

Radi, Marco; Pagano, Mafalda; Franchi, Luigi; Castagnolo, Daniele; Schenone, Silvia; Casaluce, Gianni; Zamperini, Claudio; Dreassi, Elena; Maga, Giovanni; Samuele, Alberta; Gonzalo, Encarna; Clotet, Bonaventura; Esté, José A.; Botta, Maurizio

doi:10.1002/cmdc.201200056

Cited by 12 publications

(20 citation statements)

References 32 publications

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“…Since DABO family exhibits robust antiviral activity for their high specificity and low toxicity [6,33], we compared 456 S -DABO analogs and summarized 20 of them with special high antiviral activity (TI >20,000) in Table 6 [7-9,25,34-41]. Among these analogs, compound 19 , reported by Mugnaini et al, could reach an excellent activity at picomolar (EC 50, W T =25 pM) level, indicating that S -DABO family is might be a good candidate of NNRTIs [25].…”

Section: Discussionmentioning

confidence: 99%

DB-02, a C-6-Cyclohexylmethyl Substituted Pyrimidinone HIV-1 Reverse Transcriptase Inhibitor with Nanomolar Activity, Displays an Improved Sensitivity against K103N or Y181C Than S-DABOs

Zhang

Wang

et al. 2013

PLoS ONE

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6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one (DB-02) is a member of the newly reported synthetic anti-HIV-1 compounds dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines, S-DACOs. In vitro anti-HIV-1 activity and resistance profile studies have suggested that DB-02 has very low cytotoxicity (CC50>1mM) to cell lines and peripheral blood mononuclear cells (PBMCs). It displays potent anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 2.40 to 41.8 nM). Studies on site-directed mutagenesis, genotypic resistance profiles revealed that V106A was the major resistance contributor for the compound. Molecular docking analysis showed that DB-02 located in the hydrophobic pocket with interactions of Lys101, Val106, Leu234, His235. DB-02 also showed non-antagonistic effects to four approved antiretroviral drugs. All studies indicated that DB-02 would be a potential NNRTI with low cytotoxicity and improved activity.

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Section: Discussionmentioning

confidence: 99%

DB-02, a C-6-Cyclohexylmethyl Substituted Pyrimidinone HIV-1 Reverse Transcriptase Inhibitor with Nanomolar Activity, Displays an Improved Sensitivity against K103N or Y181C Than S-DABOs

Zhang

Wang

et al. 2013

PLoS ONE

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“…HIV wild-type (WT) inhibition and cytotoxicity of TMC120 (3), the title compounds 4--7 and [8,9]. [38], difluoromethylbenzoxazole (DFMB) pyrimidine thioether 23 [39], 4,6-diamino-1,3,5-triazin-2-ol 24 [40], S-DABO 25 [41], MC1220 (26) [42], pyrimidine-based NNRTIs, MC1501 (27) and MC2082 (28) [43], indolyl aryl sulfone 29 [44], N4-(hetero)arylsulfonylquinoxalinones 30a,b [45], GW420867X (31) [46], thiazolidin-4-one 32 [47], benzyloxazole 33 [48], benzophenone GW564511 (34) [49] and catechol diether 35 [10]. The increasingly routine Incorp of fluorine atom(s) into NNRTIs candidates suggests a bright future for fluorine in antiviral drug discovery and development.…”

Section: Efficacious Roles Of the Fluorine Pharmacophore In Nnrtismentioning

confidence: 99%

Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419

Meng¹,

Liu²,

Huang³

et al. 2015

Expert Opinion on Therapeutic Patents

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Diarylpyrimidine (DAPY) derivatives, one family of HIV non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with superior activities against wild-type (WT) HIV-1 and NNRTI-resistant strains, have attracted much attention in the past decade. A series of DAPY derivatives featuring a fluorine atom on the central ring were reported as novel NNRTIs in the patent WO2014072419. Some compounds exhibited robust potency against both WT and mutant strains, which were approximately equal to or higher than those of the reference drug TMC120. Moreover, it has become evident that fluorinated molecules have a remarkable record in many other potent NNRTIs. Thus, this survey provides a sampling of renowned fluorinated NNRTIs and their mode of action, with an analysis clarifying the functional roles and impact of fluorine substitution on antiviral potency. We envision that fluorinated NNRTIs will play a continuing role in affording anti-HIV drug candidates for therapeutic applications.

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“…This is because the C-2, C-5, and C-6 substituent effects were tightly linked: the optimal moieties at positions 5 and 6 of the pyrimidine nucleus are dependent on the nature of the C-2 side chain. Some representatives from S-DABO family are compounds VIII–XII in Figure 3 , while some DABO derivatives are currently tested as microbicides or were obtained hybrids DAPY-DABO with a very good inhibitory activity [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ].…”

Section: Smiles Of Anti-hiv Pyrimidinesmentioning

confidence: 99%

Double Variational Binding—(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands

Putz

Dudaş

Isvoran

2015

IJMS

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Variational quantitative binding–conformational analysis for a series of anti-HIV pyrimidine-based ligands is advanced at the individual molecular level. This was achieved by employing ligand-receptor docking algorithms for each molecule in the 1,3-disubstituted uracil derivative series that was studied. Such computational algorithms were employed for analyzing both genuine molecular cases and their simplified molecular input line entry system (SMILES) transformations, which were created via the controlled breaking of chemical bonds, so as to generate the longest SMILES molecular chain (LoSMoC) and Branching SMILES (BraS) conformations. The study identified the most active anti-HIV molecules, and analyzed their special and relevant bonding fragments (chemical alerts), and the recorded energetic and geometric docking results (i.e., binding and affinity energies, and the surface area and volume of bonding, respectively). Clear computational evidence was also produced concerning the ligand-receptor pocket binding efficacies of the LoSMoc and BraS conformation types, thus confirming their earlier presence (as suggested by variational quantitative structure-activity relationship, variational-QSAR) as active intermediates for the molecule-to-cell transduction process.

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Synthesis, Biological Activity, and ADME Properties of Novel S‐DABOs/N‐DABOs as HIV Reverse Transcriptase Inhibitors

Cited by 12 publications

References 32 publications

DB-02, a C-6-Cyclohexylmethyl Substituted Pyrimidinone HIV-1 Reverse Transcriptase Inhibitor with Nanomolar Activity, Displays an Improved Sensitivity against K103N or Y181C Than S-DABOs

DB-02, a C-6-Cyclohexylmethyl Substituted Pyrimidinone HIV-1 Reverse Transcriptase Inhibitor with Nanomolar Activity, Displays an Improved Sensitivity against K103N or Y181C Than S-DABOs

Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419

Double Variational Binding—(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands

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