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