Identification of novel 4-substituted 7H-pyrrolo[2,3-d]pyrimidine derivatives as new FtsZ inhibitors: Bioactivity evaluation and computational simulation

Article

作者: Liu, Liwei ; Zhou, Xiang ; Yang, Linli ; Liu, Hongwu ; Fu, Xichun ; Yang, Song ; Wu, Zhibing ; Li, Ting ; Zhou, Ya

Bacterial infections and the consequent outburst of bactericide-resistance issues are fatal menace to both global health and agricultural produce. Hence, it is crucial to explore candidate bactericides with new mechanisms of action. The filamenting temperature-sensitive mutant Z (FtsZ) protein has been recognized as a new promising and effective target for new bactericide discovery. Hence, using a scaffold-hopping strategy, we designed new 7H-pyrrolo[2,3-d]pyrimidine derivatives, evaluated their antibacterial activities, and investigated their structure-activity relationships. Among them, compound B₆ exhibited the optimal in vitro bioactivity (EC₅₀ = 4.65 µg/mL) against Xanthomonas oryzae pv. oryzae (Xoo), which was superior to the references (bismerthiazol [BT], EC₅₀ = 48.67 µg/mL; thiodiazole copper [TC], EC₅₀ = 98.57 µg/mL]. Furthermore, the potency of compound B₆ in targeting FtsZ was validated by GTPase activity assay, FtsZ self-assembly observation, fluorescence titration, Fourier-transform infrared spectroscopy (FT-IR) assay, molecular dynamics simulations, and morphological observation. The GTPase activity assay showed that the final IC₅₀ value of compound B₆ against XooFtsZ was 235.0 μM. Interestingly, the GTPase activity results indicated that the B₆-XooFtsZ complex has an excellent binding constant (K_A = 10^3.24 M^-1). Overall, the antibacterial behavior suggests that B₆ can interact with XooFtsZ and inhibit its GTPase activity, leading to bacterial cell elongation and even death. In addition, compound B₆ showed acceptable anti-Xoo activity in vivo and low toxicity, and also demonstrated a favorable pharmacokinetic profile predicted by ADMET analysis. Our findings provide new chemotypes for the development of FtsZ inhibitors as well as insights into their underlying mechanisms of action.

2020-04-23·JOURNAL OF MEDICINAL CHEMISTRY

GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.

Article

作者: Walker, Jill T ; Grimes, Richard M ; Leivers, Martin R ; Xia, Bing ; Meesala, Ramu ; Remlinger, Katja ; Hamatake, Robert ; Crosby, Renae ; Miriyala, Nagaraju ; Beesu, Mallesh ; Adjabeng, George ; Kazmierski, Wieslaw M ; Baskaran, Sam

Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.

2014-12-01·ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

Potency and resistance analysis of hepatitis C virus NS5B polymerase inhibitor BMS-791325 on all major genotypes.

Article

作者: Gao, Min ; Lemm, Julie A ; Liu, Mengping ; Tuttle, Maria

BMS-791325 is a hepatitis C virus (HCV) inhibitor binding to the thumb domain of the NS5B RNA-dependent RNA polymerase. BMS-791325 is well characterized in genotype 1 (GT1) and exhibits good inhibitory activity (50% effective concentration [EC50], <10 nM) against hybrid replicons containing patient NS5B sequences from GT3a, -4a, and -5a while potency against GT2 is significantly reduced (J. A. Lemm et al., Antimicrob. Agents Chemother. 58:3485-3495, 2014, doi:http://dx.doi.org/10.1128/AAC.02495-13). BMS-791325 potency against GT6a hybrid replicons is more variable, with two of three hybrid clones having EC50s similar to that for GT1 while a third patient clone was ∼ 10 times less susceptible to BMS-791325. To characterize the resistance profile of BMS-791325 beyond GT1, curing studies were performed across GT1a and -3a to -6a and demonstrated that GT1a has the highest resistance barrier versus BMS-791325 while GT6a has the lowest. Selection of GT3 to -6 NS5B chimeric replicon cells at different concentrations of BMS-791325 revealed substitutions in the thumb domain of NS5B at residues 494 and 495 that conferred different levels of resistance to BMS-791325 but remained susceptible to NS5A or NS3 protease inhibitors. In addition, we demonstrate that the reduced potency of BMS-791325 against one GT6a patient is due to an A494 polymorphism present in ∼ 21% of sequences in the European HCV database. The results from this report suggest that BMS-791325 is a candidate for combination treatment of HCV GT3 to -6 chronic infections, and the resistance profiles identified will provide useful information for future clinical development.

100 项与 Hepatitis C virus replication inhibitors(Isis Pharmaceuticals Inc) 相关的药物交易

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