作者: Cen, Shan ; Che, Yongsheng ; Wang, Minghua ; Wang, Juxian ; Ma, Ling ; Yang, Qingqing ; Meng, Sihan ; Shan, Qi ; Wang, Yucheng ; Dong, Biao ; Zhou, Huiyu ; Gao, Yu ; Zhang, Guoning ; Zhu, Mei

Given the urgent need to combat HIV-1 drug resistance, we designed and synthesized a novel series of HIV-1 protease inhibitors with modified core scaffolds, including amino acid-linked hydroxyethyl sulfonamide, hydroxyethyl sulfonimidamide, and hydroxyethyl phosphonamidite. Most of these compounds exhibited potent activities in both enzymatic and cellular assays. Notably, compound 20a, featuring an extended l-asparagine linker, displayed an enzymatic IC₅₀ of 10 pM and an antiviral EC₅₀ of 10.4 nM. Furthermore, it maintained excellent potency against the multidrug-resistant variants (EC₅₀ = 30 ∼ 34.3 nM), demonstrating a superior resistance profile relative to Darunavir. Molecular modeling revealed that the introduction of the l-asparagine fragment promoted extensive interactions with various residues throughout the protease active site. Subsequent investigations indicated that compound 20a-D, the dipeptide prodrug of 20a, exhibited improved ADME properties. Consequently, this study highlighted the potential of core scaffold modification in generating candidates to overcome multidrug resistance and provided valuable information for further optimization.

2025-09-25·JOURNAL OF MEDICINAL CHEMISTRY

Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity

Article

作者: Qiao, Jingxin ; Flury, Philipp ; Cuell, Ashley ; Delgado, Renee ; Vishwakarma, Jyoti ; Sylvester, Katharina ; Higashi-Kuwata, Nobuyo ; Taylor, Alexander B. ; Mitsuya, Hiroaki ; Basu, Rahul ; Chen, Yan ; Dabrowska, Agnieszka K. ; Müller, Christa E. ; Harris, Reuben S. ; Pillaiyar, Thanigaimalai ; Magalhães Serafim, Mateus Sá ; O’Donoghue, Anthony J. ; Laufer, Stefan A. ; de Oliveira, Ellen Gonçalves ; Yang, Shengyong ; Gütschow, Michael

M^pro of SARS-CoV-2 plays a vital role in the replication and pathogenesis of virus. Additionally, its high conservation within the Coronaviridae family makes it an attractive therapeutic target for developing broad-spectrum agents. This study describes the design, synthesis, and structure-activity relationships of azapeptide-based SARS-CoV-2 M^pro inhibitors, leading to several compounds with nanomolar IC₅₀ values. Examples include 14r (IC₅₀ = 13.3 nM), 14s (IC₅₀ = 30.6 nM), 20a (TPG-20a, IC₅₀ = 28.0 nM), and 20g (IC₅₀ = 30.4 nM). Some compounds inhibit MERS-CoV and SARS-CoV-1 M^pro but not the human protease cathepsin L. Several inhibitors, such as 20a and 20f, exhibit antiviral activity with potencies comparable to nirmatrelvir and activity against the E166V-carrying SARS-CoV-2 variant (SARS-CoV-2^E166V). An M^pro cocrystal structure with 20a shows a covalent adduct with the catalytic Cys145. Overall, these new inhibitors are promising chemical tools that may contribute to the identification of future pan-anticoronaviral drugs.

2025-01-23·JOURNAL OF MEDICINAL CHEMISTRY

Structure-Guided Discovery of Novel N⁴-(Substituted Thiazol-2-yl)-N²-(4-Substituted phenyl)pyrimidine-2,4-Diamines as Potent CDK2 and CDK9 Dual Inhibitors with High Oral Bioavailability

Article

作者: Chen, Lin ; Li, Yanhong ; Wang, Ting ; Lin, Yukang ; Zhang, Bei ; Chen, Jingkao ; Diao, Pengcheng ; Cai, Jianfan ; Zhao, Peiliang ; Ma, Yufeng ; You, Wenwei ; Ji, Tangyang ; Zhang, Yanting

CDK2 and CDK9 play pivotal roles in cell cycle progression and gene transcription, respectively, making them promising targets for cancer treatment. Herein, we discovered a series of N⁴-(substituted thiazol-2-yl)-N²-(4-substituted phenyl)pyrimidine-2,4-diamines as highly potent CDK2/9 dual inhibitors. Especially, compound 20a significantly inhibited CDK2 (IC₅₀ = 0.004 μM) and CDK9 (IC₅₀ = 0.009 μM), achieving a 1000- and 2800-fold improvement over lead compound 11, and demonstrating broad antitumor efficacy. Mechanistic studies indicated that 20a effectively and simultaneously suppressed CDK2 and CDK9 proteins in the HCT116 cell line, leading to G2/M cell cycle arrest and cell apoptosis by regulating cell cycle- and apoptosis-related protein expression. Most importantly, 20a exhibited 86.7% oral bioavailability in rats and effectively inhibited tumor growth in HCT116 xenograft and C6 glioma rat models without significant toxicity. Overall, these observations clearly confirmed the promising therapeutic strategy of CDK2/9 dual inhibitors and provided a novel potent candidate for cancer therapy.

100 项与 Compound 20a(Shanghaitech University) 相关的药物交易

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