Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; Application of buchwald-hartwig aminations of heterocycles

Aleem Gangjee, Ojas A. Namjoshi, Sudhir Raghavan, Sherry Queener, Roy L. Kisliuk, Vivian Cody

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Opportunistic 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.

Original languageEnglish
Pages (from-to)4422-4441
Number of pages20
JournalJournal of Medicinal Chemistry
Volume56
Issue number11
DOIs
StatePublished - Jun 13 2013

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Folic Acid Antagonists
Amination
Pneumocystis carinii
Mycobacterium avium
Opportunistic Infections
Toxoplasma
Aniline Compounds
Pneumocystis Pneumonia
Acquired Immunodeficiency Syndrome
Animal Models
Morbidity
Mortality
pyrido(3,2-d)pyrimidine

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; Application of buchwald-hartwig aminations of heterocycles. / Gangjee, Aleem; Namjoshi, Ojas A.; Raghavan, Sudhir; Queener, Sherry; Kisliuk, Roy L.; Cody, Vivian.

In: Journal of Medicinal Chemistry, Vol. 56, No. 11, 13.06.2013, p. 4422-4441.

Research output: Contribution to journalArticle

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