期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 9, 期 4, 页码 386-391出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00090
关键词
Tuberculosis; siderophores; mycobactin; conformationally constrained analogues; pharmacokinetics
资金
- NIH [AI070219]
- NIAID, NIH
5'-O-[N-(Salicyl)sulfamoyl] adenosine (Sal-AMS, 1) is a nucleoside antibiotic that inhibits incorporation of salicylate into siderophores required for bacterial iron acquisition and has potent activity against Mycobacterium tuberculosis (Mtb). Cinnolone analogues exemplified by 5 were designed to replace the acidic acyl-sulfamate functional group of 1 (pK(a) = 3) by a more stable sulfonamide linkage (pK(a) = 6.0) in an attempt to address potential metabolic liabilities and improve membrane permeability. We showed 5 potently inhibited the mycobacterial salicylate ligase MbtA (apparent K-i = 12 nM), blocked production of the salicylate-capped siderophores in whole-cell Mtb, and exhibited excellent antimycobacterial activity under iron-deficient conditions (minimum inhibitor concentration, MIC = 2.3 mu M). To provide additional confirmation of the mechanism of action, we demonstrated the whole-cell activity of 5 could be fully antagonized by the addition of exogenous salicylate to the growth medium. Although the total polar surface area (tPSA) of 5 still exceeds the nominal threshold value (140 A) typically required for oral bioavailability, we were pleasantly surprised to observe introduction of the less acidic and conformationally constrained cinnolone moiety conferred improved drug disposition properties as evidenced by the 7-fold increase in volume of distribution in Sprague Dawley rats.
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