Design and synthesis of novel pyrimidine derivatives as potent antitubercular agents.

Animals Antitubercular Agents / chemical synthesis Drug Design Folic Acid Antagonists / pharmacology Mice Mice, Inbred BALB C Microbial Sensitivity Tests Mycobacterium tuberculosis / drug effects Pyrimidines / chemical synthesis Structure-Activity Relationship Sulfones / chemical synthesis Tetrahydrofolate Dehydrogenase / drug effects
Antimycobacterial Ceritinib Dihydrofolate reductase inhibitors Pyrimidine derivatives

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
01 Feb 2019
Historique:
received: 08 06 2018
revised: 30 10 2018
accepted: 21 11 2018
pubmed: 7 12 2018
medline: 12 2 2019
entrez: 4 12 2018
Statut: ppublish

Résumé

The emergence of various drug-resistant Mycobacterium tuberculosis (Mtb) strains has necessitated the exploration of new drugs that lack cross-resistance with existing therapeutics. By screening the MedChemExpress bioactive compound library, ceritinib was identified as a compound with activity against Mtb H37Ra. Ceritinib had a MIC value of 9.0 μM in vitro and demonstrated in vivo efficacy in a BALB/c mouse model infected with autoluminescent H37Ra. Then, 32 novel ceritinib derivatives were synthesized, and their antimycobacterial activities were evaluated in vitro. The antimycobacterial activities of the synthesized compounds were drastically affected by substitutions at position 4 of the pyrimidine nucleus and were enhanced by the presence of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline at position 2 of the pyrimidine nucleus. The in vivo antitubercular activities of the three most potent compounds were evaluated. 5-Chloro-N

Identifiants

DOI: 10.1016/j.ejmech.2018.11.054 PMID: 30508666
pubmed: 30508666
pii: S0223-5234(18)31013-4
doi: 10.1016/j.ejmech.2018.11.054
pii:
doi:

Substances chimiques

Antitubercular Agents 0
Folic Acid Antagonists 0
Pyrimidines 0
Sulfones 0
Tetrahydrofolate Dehydrogenase EC 1.5.1.3
ceritinib K418KG2GET

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

169-182

Informations de copyright

Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Auteurs

Pingxian Liu (P)

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.

Yang Yang (Y)

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.

Yunxiang Tang (Y)

Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China; State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510530, China.

Tao Yang (T)

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.

Zitai Sang (Z)

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.

Zhiyong Liu (Z)

State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510530, China.

Tianyu Zhang (T)

State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510530, China. Electronic address: zhang_tianyu@gibh.ac.cn.

Youfu Luo (Y)

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China. Electronic address: luo_youfu@scu.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Antituberculeux › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Conception de médicament › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Antifoliques › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée BALB C › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de sensibilité microbienne › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Bactéries › Bactéries à Gram positif › Bâtonnets à Gram positif › Bâtonnets asporogènes à Gram positif › Bâtonnets asporogènes réguliers à Gram positif › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Composés chimiques organiques › Composés du soufre › Sulfones › Design and synthesis of novel pyrimidine...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxidoreductases acting on CH-NH group donors › Dihydrofolate reductase › Design and synthesis of novel pyrimidine...