Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

被引：23

作者：

Govender, Preshendren ^{[1
]}

Muller, Rudolf ^{[1
]}

Singh, Kawaljit ^{[1
]}

Reddy, Virsinha ^{[1
]}

Eyermann, Charles J. ^{[1
]}

Fienberg, Stephen ^{[1
]}

Ghorpade, Sandeep R. ^{[1
]}

Koekemoer, Lizbe ^{[1
,2
,3
,4
]}

Myrick, Alissa ^{[1
,2
,3
,4
]}

Schnappinger, Dirk ^{[5
]}

Engelhart, Curtis ^{[5
]}

Meshanni, Jaclynn ^{[5
,6
]}

Byl, Jo Ann W. ^{[7
]}

Osheroff, Neil ^{[7
,8
,9
]}

Singh, Vinayak ^{[1
,3
,4
,10
]}

Chibale, Kelly ^{[1
,2
,3
,4
]}

Basarab, Gregory S. ^{[1
,11
]}

机构：

[1] Univ Cape Town, Drug Discovery & Dev Ctr H3D, Dept Chem, ZA-7701 Cape Town, South Africa

[2] Univ Cape Town, Dept Chem, South African Med Res Council Drug Discovery, ZA-7701 Cape Town, South Africa

[3] Univ Cape Town, Dept Chem, Dev Res Unit, ZA-7701 Cape Town, South Africa

[4] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Cape Town, South Africa

[5] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA

[6] Rutgers State Univ, Dept Pharmacol & Toxicol, Ernest Mario Sch Pharm, Piscataway, NJ 08854 USA

[7] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA

[8] Vanderbilt Univ, Sch Med, Dept Med Hematol Oncol, Nashville, TN 37232 USA

[9] VA Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA

[10] Univ Cape Town, Drug Discovery & Dev Ctr H3D, South African Med Res Council Drug Discovery, ZA-7701 Cape Town, South Africa

[11] Univ Cape Town, Dept Med, Div Clin Pharmacol, Drug Discovery & Dev Ctr H3D, ZA-7935 Cape Town, South Africa

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 09期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

MYCOBACTERIUM-TUBERCULOSIS GYRASE; ACCURATE DOCKING; QUINOLONE ACTION; TOPOISOMERASE; OPTIMIZATION; MOXIFLOXACIN; RESISTANCE; COMPLEXES; CANDIDATE; DISCOVERY;

D O I：

10.1021/acs.jmedchem.2c00266

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New antibiotics with either a novel mode of actionor novel mode of inhibition are urgently needed to overcome thethreat of drug-resistant tuberculosis (TB). The present studyprofiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitorshaving activity against drug-resistantMycobacterium tuberculosis(Mtb), the causative agent of TB. While the clinical candidatezoliflodacin has progressed to phase 3 trials for the treatment ofgonorrhea, compounds herein demonstrated higher inhibitorypotency againstMtbDNA gyrase (e.g., compound42with IC50=2.0) and lowerMtbminimum inhibitor concentrations (0.49 mu Mfor42). Notably,42and analogues showed selectiveMtbactivityrelative to representative Gram-positive and Gram-negativebacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA, while on-target activity was supportedby hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs withMtbDNA gyrase was developed, and astructural hypothesis was built for structure-activity relationship expansion

引用

页码：6903 / 6925

页数：23

共 53 条

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