Ali Amjad, Taylor Gayle E, Ellsworth Ken, Harris Georgianna, Painter Ronald, Silver Lynn L, Young Katherine
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
J Med Chem. 2003 May 8;46(10):1824-30. doi: 10.1021/jm020483c.
6-Anilinopyrazolo[3,4-d]pyrimidin-4-ones are novel dGTP analogues that inhibit the replication-specific enzyme DNA polymerase III (DNA pol III) of Staphlococcus aureus and other Gram-positive (Gr+) bacteria. To enhance the potential of these inhibitors as antimicrobial agents, a structure-activity relationship was developed involving substitutions at the 2, 4, and pyrazolo NH positions. All of the new inhibitors were tested for their ability to inhibit S. aureus DNA pol III and the growth of several other Gr+ bacteria in culture. 2-Anilino groups with small hydrophobic groups in the meta or para position enhanced both antipolymerase and antimicrobial activity. 2-Benzyl-substituted inhibitors were substantially less active. Substitution in the 4-position by oxygen gave the optimal activity, whereas substitution at the pyrazolo NH was not tolerated. These pyrazolo[3,4-d]pyrimidine derivatives represent a novel class of antimicrobials with promising activities against Gr+ bacteria.
6-苯胺基吡唑并[3,4-d]嘧啶-4-酮是一类新型的dGTP类似物，可抑制金黄色葡萄球菌和其他革兰氏阳性（Gr+）细菌的复制特异性酶DNA聚合酶III（DNA pol III）。为了提高这些抑制剂作为抗菌剂的潜力，开展了一项构效关系研究，涉及在2、4和吡唑并氮氢位置进行取代。所有新抑制剂都测试了其抑制金黄色葡萄球菌DNA pol III的能力以及在培养物中抑制其他几种Gr+细菌生长的能力。在间位或对位带有小疏水基团的2-苯胺基增强了抗聚合酶和抗菌活性。2-苄基取代的抑制剂活性明显较低。在4位用氧取代可获得最佳活性，而吡唑并氮氢位置的取代则不能耐受。这些吡唑并[3,4-d]嘧啶衍生物代表了一类新型抗菌剂，对Gr+细菌具有有前景的活性。
