Document Detail


Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; application of Buchwald-Hartwig aminations of heterocycles.
MedLine Citation:
PMID:  23627352     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Aleem Gangjee; Ojas A Namjoshi; Sudhir Raghavan; Sherry F Queener; Roy L Kisliuk; Vivian Cody
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-05-21
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-13     Completed Date:  2013-08-20     Revised Date:  2014-06-16    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4422-41     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
PDB/4IXE;  4IXF;  4IXG
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MeSH Terms
Descriptor/Qualifier:
Amination
Aniline Compounds / chemistry
Crystallography, X-Ray
Drug Design
Folic Acid Antagonists / chemical synthesis*,  chemistry
Humans
Models, Molecular*
Mycobacterium avium / enzymology
Pneumocystis carinii / enzymology
Pneumocystis jirovecii / enzymology
Pyridines / chemical synthesis*,  chemistry
Pyrimidines / chemical synthesis*,  chemistry
Recombinant Proteins / chemistry
Species Specificity
Structure-Activity Relationship
Tetrahydrofolate Dehydrogenase / chemistry
Grant Support
ID/Acronym/Agency:
AI069966/AI/NIAID NIH HHS; R01 AI069966/AI/NIAID NIH HHS; R01 AI098458/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Aniline Compounds; 0/Folic Acid Antagonists; 0/Pyridines; 0/Pyrimidines; 0/Recombinant Proteins; EC 1.5.1.3/Tetrahydrofolate Dehydrogenase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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