Bioisosterism-based design and enantiomeric profiling of chiral hydroxyl-substituted biphenyl-diarylpyrimidine nonnucleoside HIV-1 reverse transcriptase inhibitors

Chen, Xiaomei; Tao, Yuan; Pannecouque, Christophe; Clercq, Erik De; Zhuang, Chunlin; Chen, Fen‐Er

doi:10.1016/j.ejmech.2020.112549

Cited by 17 publications

(23 citation statements)

References 28 publications

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“…Electrocardiogram (ECG) was demonstrated to be another rational method to predict the cardiotoxicity of drugs 89 . Very recently, our group investigated the cardiac toxicity of 12 (Figure 5) by the ECG 29 . Compound 12 displayed a similar ECG signals between the intragastric administration at a dose of 2 g/kg in mice with control group.…”

Section: Safety Inspectionmentioning

confidence: 99%

“…Compound 10 displayed excellent activity (EC 50 = 5.3 nM against WT HIV‐1), which was 12‐fold more potent than 11 and higher than racemic 9 21 . Another biphenyl DAPYs with chiral hydroxyl groups were further discovered and this kind of compounds have revealed significant activities against multiple strains and relatively low cytotoxicity 29 . Compound 14 possessed submicromlar activities against WT, five kinds of single mutant strains (K103N, L100I, Y181C, E138K; especially Y188L), and two kinds of double mutant virus strains (F227L + V106A, RES056).…”

Section: Improvement On Pharmacodynamicsmentioning

confidence: 99%

“…Modification of the linker could adjust the molecular flexibility, 36 restrict the conformation, 20 and form compensatory hydrogen‐bonding interactions with surrounding residues, 29 further resulting in an enhanced the antiviral activity against WT strain and multiple resistant mutants. The monoatomic carbon linker had a superiority in molecular diversity, generating compounds with significantly higher antiviral activities than diatomic linker.…”

Section: Improvement On Pharmacodynamicsmentioning

confidence: 99%

“…In summary, SI, acute toxicity index, HE staining of organ tissues, ECG, hERG toxicity, and neuron morphometry were considered as important parameters for evaluating the safety of drugs 20,29,96 . And the in vivo and in vitro tests should be integrated as appropriate (Figure 21).…”

Section: Safety Inspectionmentioning

confidence: 99%

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Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

Zhuang

Chen

2021

Medicinal Research Reviews

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Drug discovery of human immunodeficiency virus (HIV) is a hot field in medicinal chemistry community for many years. The diarylpyrimidines (DAPYs) are the second‐generation non‐nucleoside reverse transcriptase inhibitors (NNRTIs) targeting reverse transcriptase, playing a great irreplaceable role in HIV transcriptional therapy. However, fast‐growing drug‐resistant mutations as nonnegligible challenge are still unpredictably appeared in the clinical practice, leading to deactivate or reduce the existing drugs. In the last 20 years, more and more novel DAPY derivatives have developed with the purpose to counter the mutants. Nevertheless, most of them have dissatisfactory pharmacokinetics (PK) or poor antiviral activity toward resistant mutant strains. In this article, we will analyze the NNRTI derivatives with promising druggability, and summarize a series of druggability modification strategies to improve the antiviral activity, reduce toxicity and improve the PK properties in recent years. The prospects of DAPYs and the directions for future efforts will be discussed.

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Section: Safety Inspectionmentioning

confidence: 99%

Section: Improvement On Pharmacodynamicsmentioning

confidence: 99%

Section: Improvement On Pharmacodynamicsmentioning

confidence: 99%

Section: Safety Inspectionmentioning

confidence: 99%

See 2 more Smart Citations

Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

Zhuang

Chen

2021

Medicinal Research Reviews

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“…8 However, replacement of the NH by a hydroxy group as the linker indicated a poor metabolic stability that cannot be accurately measured. 10 Thus, the linker of biphenyl DAPYs were assumed to be an very important aspect affecting the metabolic, PK and cytotoxicity. In the present study, we still focused on the linker by alkylation design in order to block the potential metabolic sensitive sites and maintain the high antiviral potency.…”

Section: Introductionmentioning

confidence: 99%

Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N-Alkylation to Methyl Hopping on the Pyrimidine Ring

et al. 2021

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Considering the non-ideal metabolic stability of the difuloro-biphenyl-diarylpyrimidine lead compound 4, a series of novel alkylated difuloro-biphenyl-diarylpyrimidines were structure-based designed and synthesized as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). Introducing alkyl or substituted alkyl groups on the linker region (consist of V179, Y181, E138 residues) to block the potential metabolic sensitive sites obtained twenty-two derviatives. Among them, compound 12a with N-methyl group displayed excellent HIV-1 inhibitory activity (EC 50 = 6.16 nM), moreover, a significant improvement in the selectivity (SI = 24,069) compared with existing drugs (NVP, SI > 72; ETR, SI > 1159; EFV, SI > 1600). Finally, the methyl group was hopped to the central pyrimidine ring in order to occupy the small linker region and maintain the water-mediated hydrogen bond observed in the binding of compound 4 with RT. The resulting compound 16y exhibited an improved HIV-1 inhibitory activity (EC 50 = 1.37 nM) and much lower cytotoxicity with the SI > 208,333). In addition, compound 16y possessed nanomolar activity toward multiple single-mutant virus strains except Y188L. For the metabolic stability, compound 16y have a better stability in human liver microsomes (T 1/2 = 138 min, Cl int = 5.0 μL/min/mg) than compounds 4 (T 1/2 = 44 min, Cl int = 16 μL/min/mg). No apparent in vivo acute toxicity was observed in 16y-treated female, and especially pregnant mice. The molecular docking studies predicted the binding modes of 16y with RT, and the methyl group was displayed as occupying effect in the hydrophobic pocket, explaining the activity differences for 16y and the precursor 12a. This series of alkylated compounds with highly potency and safety represent promising lead template for future discovery.

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Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Xu,

Wang,

2024

Archiv der Pharmazie

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Cancer, characterized by uncontrolled cell growth and metastasis, is responsible for nearly one in six deaths and represents a severe threat to public health worldwide. Chemotherapy can substantially improve the quality of life and survival of patients with cancer, but anticancer chemotherapeutics are associated with a range of adverse effects. Moreover, almost all currently available anticancer chemotherapeutics could develop drug resistance over a period of time of application in cancer patients and ultimately lead to cancer relapse and death in 90% of patients, creating an urgent need to develop new anticancer agents. Fused pyrimidines trait the inextricable part of DNA and RNA and are vital in numerous biological processes. Fused pyrimidines can act on various biological cancer targets and have the potential to address drug resistance. In addition, more than 20 fused pyrimidines have already been approved for clinical treatment of different cancers and occupy a prominent place in the current therapeutic arsenal, revealing that fused pyrimidines are privileged scaffolds for the development of novel anticancer chemotherapeutics. The purpose of this review is to summarize the current scenario of fused pyrimidines with in vivo anticancer therapeutic potential along with their acute toxicity, metabolic profiles as well as pharmacokinetic properties, toxicity and mechanisms of action developed from 2020 to the present to facilitate further rational exploitation of more effective candidates.

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Bioisosterism-based design and enantiomeric profiling of chiral hydroxyl-substituted biphenyl-diarylpyrimidine nonnucleoside HIV-1 reverse transcriptase inhibitors

Cited by 17 publications

References 28 publications

Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N-Alkylation to Methyl Hopping on the Pyrimidine Ring

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

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