Design, Synthesis, and Molecular Modeling of Novel Pyrido[2,3‑<i>d</i>]pyrimidine Analogues As Antifolates; Application of Buchwald–Hartwig Aminations of Heterocycles

Abstract

Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, <i>pj</i>), Toxoplasma gondii (T. gondii, <i>tg</i>), and Mycobacterium avium (M. avium, <i>ma</i>) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of <i>pj</i>DHFR and <i>tg</i>DHFR make the design of inhibitors challenging. A novel series of pyrido­[2,3-<i>d</i>]­pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald–Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido­[2,3-<i>d</i>]­pyrimidine was successfully explored to synthesize these analogues. Compound <b>26</b> was the most selective inhibitor with excellent potency against <i>pj</i>DHFR. Molecular modeling studies with a <i>pj</i>DHFR homology model explained the potency and selectivity of <b>26</b>. Structural data are also reported for <b>26</b> with <i>pc</i>DHFR and <b>16</b> and <b>22</b> with variants of <i>pc</i>DHFR