Further studies on 2,4-Diamino-5-(2′,5′-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS
Further studies on 2,4-Diamino-5-(2′,5′-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS
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DOI：
10.1021/jm020466n
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发表时间：
2003-04-24
影响因子：
7.3
通讯作者：
Queener, SF
中科院分区：
文献类型：
--
作者：
Rosowsky, A;Forsch, RA;Queener, SF
作为不断发现新型小分子抗叶酸剂的一部分，该新型小分子抗叶酸剂将甲氧苄啶 (TMP) 的酶结合物种选择性与吡曲辛 (PTX) 的效力相结合，合成了 10 种先前未报道的 2,4-二氨基-5-(2'-甲氧基-5'-取代)苄基嘧啶 (2-11)，其 5'-取代基远端含有羧基，并测试作为卡氏肺囊虫 (Pc)、弓形虫 (Tg) 和鸟分枝杆菌 (Ma) 的二氢叶酸还原酶 (DHFR) 的抑制剂，这三种机会性病原体通常会导致因 HIV 感染或免疫抑制化疗而导致免疫系统受损的人罹患危及生命的疾病。通过比较每种化合物对抗寄生虫酶的效力与其对抗大鼠肝脏DHFR的效力来评估DHFR抑制的选择性指数。 2,4-Diamino-5-[5'-(5-carboxy-1-pentynyl)-2'-methoxybenzyl]-pyrimidine (3) 抑制 Pc DHFR，选择性指数为 79，比 TMP 有效 430 倍。 2,4-二氨基-5-[5'-(4-羧基-1-丁炔基)-2'-甲氧基苄基]嘧啶(2)，侧链碳原子数比3少1个，对Ma DHFR的选择性指数为910，比TMP强43倍。 2,4-二氨基-5-[5'-(5-羧基戊基)-2'-甲氧基苄基]嘧啶 (6) 对 Tg DHFR 的选择性指数为 490，比 TMP 强 320 倍。 2,4-二氨基-5-[5'-(6-羧基-1-己炔基)-2'-甲氧基苄基]嘧啶 (4) 比 3 多一个碳，对所有三种寄生虫酶的效力均低于 3 或 6，并且对 Pc 酶的选择性指数也比 3 低。然而，4 是该系列中唯一对 Tg 和 Ma DHFR 选择性指数 >300 的成员。鉴于 PTX 对抗大鼠 DHFR 的效力至少比对抗卡氏疟原虫或刚地弓形虫 DHFR 的效力强 10 倍，并且其中几种化合物的选择性指数与 TMP 和 PTX 相当或超过，我们的结果表明，有可能开发出临床上有用的非经典抗叶酸剂，对艾滋病的主要机会病原体既有效又具有选择性。
As part of an ongoing effort to discover novel small-molecule antifolates combining the enzyme-binding species selectivity of trimethoprim (TMP) with the potency of piritrexim (PTX), 10 previously unreported 2,4-diamino-5-(2'-methoxy-5'-substituted)benzylpyrimidines (2-11) containing a carboxyl group at the distal end of the 5'-substituent were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic pathogens frequently responsible for life-threatening illness in people with impaired immune systems as a result of HIV infection or immunosuppressive chemotherapy. The selectivity index of DHFR inhibition was evaluated by comparing the potency of each compound against the parasite enzymes with its potency against rat liver DHFR. 2,4-Diamino-5-[5'-(5-carboxy-1-pentynyl)-2'-methoxybenzyl]-pyrimidine (3) inhibited Pc DHFR with a selectivity index of 79 and was 430 times more potent than TMP. 2,4-Diamino-5-[5'-(4-carboxy-1-butynyl)-2'-methoxybenzyl]pyrimidine (2), with one less carbon than 3 in the side chain, had a selectivity index of 910 against Ma DHFR and was 43 times more potent than TMP. 2,4-Diamino-5-[5'-(5-carboxypentyl)-2'-methoxybenzyl]pyrimidine (6) had a selectivity index of 490 against Tg DHFR and was 320 times more potent than TMP. 2,4-Diamino-5-[5'-(6-carboxy-1-hexynyl)-2'-methoxybenzyl]pyrimidine (4), with one more carbon than 3, was less potent against all three of the parasite enzymes than either 3 or 6 and also had a lower selectivity index than 3 against the Pc enzyme. However, 4 was the only member of the series with a selectivity index of >300 against both Tg and Ma DHFR. Given that PTX is at least 10 times more potent against rat DHFR than against P. carinii or T. gondii DHFR and that the selectivity index of several of the compounds matches or exceeds that of TMP as well as PTX, our results suggest that it may be possible to develop clinically useful nonclassical antifolates that are both potent and selective against the major opportunistic pathogens of AIDS.