Dawadi Surendra, Boshoff Helena I M, Park Sae Woong, Schnappinger Dirk, Aldrich Courtney C
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, United States.
ACS Med Chem Lett. 2018 Mar 16;9(4):386-391. doi: 10.1021/acsmedchemlett.8b00090. eCollection 2018 Apr 12.
5'--[-(Salicyl)sulfamoyl]adenosine (Sal-AMS, ) is a nucleoside antibiotic that inhibits incorporation of salicylate into siderophores required for bacterial iron acquisition and has potent activity against (). Cinnolone analogues exemplified by were designed to replace the acidic acyl-sulfamate functional group of (p = 3) by a more stable sulfonamide linkage (p = 6.0) in an attempt to address potential metabolic liabilities and improve membrane permeability. We showed potently inhibited the mycobacterial salicylate ligase MbtA (apparent = 12 nM), blocked production of the salicylate-capped siderophores in whole-cell , and exhibited excellent antimycobacterial activity under iron-deficient conditions (minimum inhibitor concentration, MIC = 2.3 μM). To provide additional confirmation of the mechanism of action, we demonstrated the whole-cell activity of could be fully antagonized by the addition of exogenous salicylate to the growth medium. Although the total polar surface area (tPSA) of still exceeds the nominal threshold value (140 Å) 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.
5'-[-(水杨酰基)氨磺酰基]腺苷（Sal-AMS）是一种核苷类抗生素，它能抑制水杨酸盐掺入细菌获取铁所需的铁载体中，并且对[具体细菌名称未给出]具有强大的活性。以[具体化合物名称未给出]为代表的肉桂酮类似物被设计用来将[具体化合物名称未给出]（p = 3）的酸性酰基氨磺酸盐官能团替换为更稳定的磺酰胺连接（p = 6.0），试图解决潜在的代谢问题并提高膜通透性。我们发现[具体化合物名称未给出]能有效抑制分枝杆菌水杨酸盐连接酶MbtA（表观Kd = 12 nM），阻断全细胞[具体细胞名称未给出]中水杨酸盐封端的铁载体的产生，并且在缺铁条件下表现出优异的抗分枝杆菌活性（最低抑菌浓度，MIC = 2.3 μM）。为了进一步证实作用机制，我们证明了在生长培养基中添加外源性水杨酸盐可完全拮抗[具体化合物名称未给出]的全细胞活性。尽管[具体化合物名称未给出]的总极性表面积（tPSA）仍然超过了口服生物利用度通常所需的标称阈值（140 Å），但我们惊喜地发现，引入酸性较弱且构象受限的肉桂酮部分赋予了更好的药物处置特性，这在Sprague-Dawley大鼠中的分布体积增加7倍得到了证明。
