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PDBsum entry 4ixe
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Oxidoreductase/inhibitor
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PDB id
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4ixe
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References listed in PDB file
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Key reference
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Title
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Design, Synthesis, And molecular modeling of novel pyrido[2,3-D]pyrimidine analogues as antifolates; application of buchwald-Hartwig aminations of heterocycles.
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Authors
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A.Gangjee,
O.A.Namjoshi,
S.Raghavan,
S.F.Queener,
R.L.Kisliuk,
V.Cody.
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Ref.
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J Med Chem, 2013,
56,
4422-4441.
[DOI no: ]
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PubMed id
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Abstract
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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.
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