Design and synthesis of novel pyrimidine derivatives as potent antitubercular agents
| Autor: | Tao Yang, Zitai Sang, Zhiyong Liu, Tianyu Zhang, Pingxian Liu, Yang Yang, Youfu Luo, Yunxiang Tang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Drug
Pyrimidine medicine.drug_class media_common.quotation_subject In silico Antitubercular Agents Microbial Sensitivity Tests Antimycobacterial 01 natural sciences Mycobacterium tuberculosis Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Drug Discovery Dihydrofolate reductase medicine Animals Sulfones 030304 developmental biology media_common Pharmacology Mice Inbred BALB C 0303 health sciences biology Ceritinib 010405 organic chemistry Organic Chemistry General Medicine biology.organism_classification Bioactive compound 0104 chemical sciences Tetrahydrofolate Dehydrogenase Pyrimidines chemistry Biochemistry Drug Design biology.protein Folic Acid Antagonists medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 163:169-182 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.11.054 |
| Popis: | 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-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(naph thalen-1-yl) pyrimidine-2,4-diamine (16j) remarkably reduced the Mtb burden of mice. This result suggested the potential of 16j as a novel drug with superior antitubercular activities. The results of experiments on the combination of sulfamethoxazole with 16j and in silico modeling suggest that dihydrofolate reductase is the potential molecular target of 16j. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect