Design, synthesis and molecular modeling of novel pyrido[2,3-d]pyrimidine analogs as antifolates: Application of Buchwald-Hartwig aminations of heterocycles

dc.contributor.authorGangjee, Aleem
dc.contributor.authorNamjoshi, Ojas A.
dc.contributor.authorRaghavan, Sudhir
dc.contributor.authorQueener, Sherry F.
dc.contributor.authorKisliuk, Roy L.
dc.contributor.authorCody, Vivian
dc.contributor.departmentPharmacology and Toxicology, School of Medicine
dc.date.accessioned2025-05-09T11:52:54Z
dc.date.available2025-05-09T11:52:54Z
dc.date.issued2013
dc.description.abstractOpportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg), and Mycobacterium avium (M. avium, ma) 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 pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]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-d]pyrimidine was successfully explored to synthesize these analogues. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationGangjee A, Namjoshi OA, Raghavan S, Queener SF, Kisliuk RL, Cody V. Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; application of Buchwald-Hartwig aminations of heterocycles. J Med Chem. 2013;56(11):4422-4441. doi:10.1021/jm400086g
dc.identifier.urihttps://hdl.handle.net/1805/47924
dc.language.isoen_US
dc.publisherACS
dc.relation.isversionof10.1021/jm400086g
dc.relation.journalJournal of Medicinal Chemistry
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectPyridines
dc.subjectPyrimidines
dc.subjectAniline compounds
dc.subjectPneumocystis carinii
dc.titleDesign, synthesis and molecular modeling of novel pyrido[2,3-d]pyrimidine analogs as antifolates: Application of Buchwald-Hartwig aminations of heterocycles
dc.typeArticle
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