Lead Optimization of Diarylpyrimidines as Non‐nucleoside Inhibitors of HIV‐1 Reverse Transcriptase

Zeng, Zhao‐Sen; Liu, Yonghong; Feng, Xingyu; Chen, Fen‐Er; Pannecouque, Christophe; Balzarini, Jan; Clercq, Erik De

doi:10.1002/cmdc.201000045

Cited by 30 publications

(15 citation statements)

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“…Incorporating a CN linkage between ring A and the central pyrimidine ring B was determined to be an effective strategy for developing novel DAPY analogues with promising antiviral potency. For instance, compound 1 was a new CN-DAPY with promising anti-HIV potency and selectivity (EC 50 = 1.8 nM, SI > 118595) ( Figure 2) [23]. The biphenyl-DAPYs were developed by our group with low nanomolar EC 50 values against the WT HIV-1 strain and several clinically resistant strains [24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

et al. 2020

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The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure–activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.

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Section: Introductionmentioning

confidence: 99%

Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

et al. 2020

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“…In case of dual inhibitors, the chelating triad of Mg 2+ can be included in pyrimidine core (used an uracil core, [C/N positionX ]): [C p2 ]O-[N p3 ]H(or OH)-[C p4 ]O, where the groups of benzyl or dimethyl-benzyl are bounded in N-1 or C-6 positions [ 20 , 21 , 22 , 118 ]. However, for the actual majority of pyrimidine derivatives NNRTIs inhibitors with an excellent anti-HIV-1 activity of HIV-1 (as HEPT, DABO, DAPY) the following findings are specific [ 21 , 28 , 39 , 40 , 48 , 50 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 89 , 90 , 119 , 120 ]: The position of the molecule is in the hydrophobic region of the NNRTI binding site/hydrophobic interactions (by π–π, π-CH, van der Waals contacts) having as two major substituents of the pyrimidine core the residues Tyr181, Tyr188, Phe227, Trp229, His235, Pro238 and/or Val106; The –CH 2 – linker of benzyl group or methyl group bound to the benzene ring is positioned closely to Glu138 from the p51 domain of RT, while the pyrimidine core is positioned in the area between Leu100 and Val179; The formation of one or more H-bonds with Lys101 (and/or Lys103) where there are possible; The Ar-H interactions with Leu234 are often observed. …”

Section: Discussion: Variational Binding-conformational Analysismentioning

confidence: 99%

“…Since DAPY NNRTI inhibitors were first produced, many derivatives with modifications on the structural diversity of the linker between the right benzene ring and the central pyrimidine ring have been developed. The left wing of the DAPY structure was confirmed as the indispensable pharmacophore, e.g., the related compounds CH-DAPY, CH(OH)-DAPY, CR(OH)-DAPY, CH(CN)-DAPY, C(=NOH)-DAPY, O-DAPY, pDAPY–piperidinylamino-diarylpyrimidine, and CAPY–cycloalkyl arylpyrimidines [ 37 , 50 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ].…”

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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“…The synthetic route of the target compounds A1-A12 and B1-B6 are depicted in Scheme 1. The key intermediates 4-(4-chloro-pyrimidin-2-ylamino)benzonitriles (10) were prepared from compound (7) according to our previously reported three-step protocol [23]. The substituted 4-cyanophenylacetonitriles 6a-l were synthesized via a one-pot procedure from 5a-l. Then, compounds 6a-l were reacted with key intermediates (10) to yield the target CH(CN)-DAPYs.…”

Section: Chemistrymentioning

confidence: 99%

Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs

Pannecouque

Clercq

et al. 2020

Molecules

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Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds B4 (EC50 = 6 nM) and B6 (EC50 = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC50 values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC50 = 0.08 μM). The preliminary structure–activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.

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Lead Optimization of Diarylpyrimidines as Non‐nucleoside Inhibitors of HIV‐1 Reverse Transcriptase

Cited by 30 publications

References 15 publications

Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

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

Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs

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