Semisynthetic Antimycobacterial C-3 Silicate and C-3/C-21 Ester Derivatives of Fusidic Acid: Pharmacological Evaluation and Stability Studies in Liver Microsomes, Rat Plasma, and Mycobacterium tuberculosis culture

被引:25
|
作者
Njoroge, Mathew [1 ]
Kaur, Gurminder [1 ]
Espinoza-Moraga, Marlene [1 ]
Wasuna, Antonina [1 ]
Dziwornu, Godwin Akpeko [1 ]
Seldon, Ronnett [2 ,3 ]
Taylor, Dale [3 ]
Okombo, John [1 ,8 ]
Warner, Digby F. [2 ,4 ,5 ,6 ]
Chibale, Kelly [1 ,2 ,3 ,7 ]
机构
[1] Univ Cape Town, Dept Chem, ZA-7701 Rondebosch, South Africa
[2] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South Africa
[3] Univ Cape Town, Drug Discovery & Dev Ctr H3D, ZA-7701 Rondebosch, South Africa
[4] Univ Cape Town, Fac Hlth Sci, SAMRC NHLS UCT Mol Mycobacteriol Res Unit, DST NRF Ctr Excellence Biomed TB Res,Dept Pathol, ZA-7701 Rondebosch, South Africa
[5] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South Africa
[6] Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, ZA-7701 Rondebosch, South Africa
[7] Univ Cape Town, South African Med Res Council, Drug Discovery & Dev Res Unit, ZA-7701 Rondebosch, South Africa
[8] Columbia Univ, Dept Microbiol & Immunol, Irving Med Ctr, Hammer Hlth Sci Ctr 1502, New York, NY 10032 USA
来源
ACS INFECTIOUS DISEASES | 2019年 / 5卷 / 09期
基金
英国医学研究理事会;
关键词
tuberculosis; fusidic acid; metabolism; prodrug; silicate; hydrolysis; VITRO SUSCEPTIBILITY; AMIDE DERIVATIVES; PHARMACOKINETICS; GROWTH; ASSAY; COMBINATION; INHIBITION; PRODRUGS; COMPLEX; PROTEIN;
D O I
10.1021/acsinfecdis.9b00208
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Fusidic acid (FA), a natural product fusidane triterpene-based antibiotic with unique structural features, is active in vitro against Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). While possessing good pharma-cokinetics in man, FA is rapidly metabolized in rodents, thus complicating proof-of-concept studies in this model. Toward the repositioning of FA as an anti-TB agent, we herein describe the synthesis, activity, and metabolism of FA and semisynthesized ester derivatives in rat liver microsomes, rat plasma, and mycobacterial cell culture. FA and derivative molecules with a free C-3 OH underwent species-specific metabolism to the corresponding 3-OH epimer, 3-epifusidic acid (3-epiFA). FA was also metabolized in rat plasma to form FA lactone. These additional routes of metabolism may contribute to the more rapid clearance of FA observed in rodents. C-3 alkyl and aryl esters functioned as classic prodrugs of FA, being hydrolyzed to FA in microsomes, plasma, and Mycobacterium tuberculosis culture. In contrast, C-3 silicate esters and C-21 esters were inert to hydrolysis and so did not act as prodrugs. The antimycobacterial activity of the C-3 silicate esters was comparable to that of FA, and these compounds were stable in microsomes and plasma, identifying them as potential candidates for evaluation in a rodent model of tuberculosis.
引用
收藏
页码:1634 / 1644
页数:21
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