Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS).
Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS).
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DOI：
10.1016/j.ejmech.2022.114201
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发表时间：
2022-03-15
影响因子：
6.7
通讯作者：
Aldrich CC
中科院分区：
文献类型：
--
作者：
Hegde PV;Howe MD;Zimmerman MD;Boshoff HIM;Sharma S;Remache B;Jia Z;Pan Y;Baughn AD;Dartois V;Aldrich CC
结核病（TB）是世界上最致命的传染病之一，每年造成近130万人死亡，感染近四分之一的人口。对氨基水杨酸（PAS）是治疗耐药结核分枝杆菌的重要二线药物，生物利用度中等，清除速度快，每天需要高剂量，最高可达12克。这反过来又引起严重的胃肠道紊乱，可能是由于肠道微生物群和宿主上皮细胞的破坏。我们首先合成了一系列烷基、酰基和烷基氧羰基氧基烷基酯前药，以提高口服生物利用度，从而防止肠道积聚以及肠道微生物群对具有细胞毒性的非天然叶酸物种的不良生物激活。PAS的枢轴酯前药优于所有前药，并表现出接近定量的吸收。虽然概念上简单的前药方法提高了PAS的口服生物利用度，但它并没有解决n -乙酰转移酶-1 （NAT-1）介导的PAS内在的快速清除问题。因此，我们接下来修改了PAS支架，通过引入基团来立体阻断n -乙酰化和PAS芳基环的氟化，从而通过电子失活对氨基来减弱n -乙酰化，从而减少NAT-1催化的失活。在制备的单氟化类似物中，5-氟- pas表现出最好的活性，并且通过口服给药CD-1小鼠的曲线下面积（AUC）测量，NAT-1的失活率降低了11倍，这意味着暴露率提高了5倍。pivot - yl前药和PAS 5位的氟化解决了PAS的主要局限性，并有可能使这种二线结核病药物重新焕发活力。
Tuberculosis (TB) is one of the world’s most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population, para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 grams per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.
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影响因子：
8.6
作者：
Hajian, Behnoush;Scocchera, Eric;Wright, Dennis
通讯作者：
Wright, Dennis
DOI：
10.1016/j.ijid.2021.02.107
发表时间：
2021-12
期刊：
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
影响因子：
--
作者：
Chakaya J;Khan M;Ntoumi F;Aklillu E;Fatima R;Mwaba P;Kapata N;Mfinanga S;Hasnain SE;Katoto PDMC;Bulabula ANH;Sam-Agudu NA;Nachega JB;Tiberi S;McHugh TD;Abubakar I;Zumla A
通讯作者：
Zumla A
影响因子：
5.2
作者：
Dawadi, Surendra;Kordus, Shannon L.;Aldrich, Courtney C.
通讯作者：
Aldrich, Courtney C.
影响因子：
3.6
作者：
Bhagwanth, Swapna;Waterson, Alex G.;Hornberger, Keith R.
通讯作者：
Hornberger, Keith R.
影响因子：
3.2
作者：
Bernheim, F
通讯作者：
Bernheim, F