New tetrahydropyrimidine-1,2,3-triazole clubbed compounds: Antitubercular activity and Thymidine Monophosphate Kinase (TMPKmt) inhibition

• Published in: Bioorganic chemistry 2023-02, Vol.131, p.106312-106312, Article 106312
• Main Authors: El-Shoukrofy, Mai S., Atta, Amal, Fahmy, Salwa, Sriram, Dharmarajan, Mahran, Mona A., Labouta, Ibrahim M.
• Format: Article
• Language: English
• Subjects: 1,2,3-triazole; Animals; Antitubercular activity; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Cytotoxicity against RAW 264.7 cells; Docking study; Drug-likeness model score; Mice; Microbial Sensitivity Tests; Microplate alamar blue assay; Molecular Docking Simulation; Mycobacterium tuberculosis; Nucleoside-Phosphate Kinase; Structure-Activity Relationship; Tetrahydropyrimidine; Thymidine monophosphate kinase inhibitors; Triazoles - chemistry
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.106312

[Display omitted] •Tetrahydropyrimidine-triazole hybrids were designed via molecular hybridization.•2 sets of hybrids were synthesized using click chemistry then Biginelli reaction.•6 compounds of better anti-TB activity than pyrazinamide & 6 of comparable activity.•The most active compounds were non-toxic against RAW 264.7 mouse macrophage cells.•Active compounds were TMPKmt inhibitors &in silico studies were discussed. Two series of new tetrahydropyrimidine (THPM)-1,2,3-triazole clubbed compounds were designed, synthesized and screened for their antitubercular (anti-TB) activity against M. tuberculosis H37Rv strain using microplate alamar blue assay (MABA). The most active compounds 5c, 5d, 5e and 5f were further examined for their cytotoxicity against the growth of RAW 264.7 mouse macrophage cells using MTT assay. The four compounds showed safety profiles better than or comparable to that of ethambutol (EMB). These compounds were evaluated for their inhibition activity against mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Compounds 5c and 5e were the most potent exhibiting comparable inhibition activity to that of the natural substrate deoxythymidine monophosphate (dTMP). An in silico study was performed including docking of the most active compounds 5c and 5e into the TMPKmt (PDB: ID 1G3U) binding pocket in addition to prediction of their physicochemical and pharmacokinetic properties to explore the overall activity of these anti-TB candidates. Compounds 5c and 5e are promising anti-TB agents and TMPKmt inhibitors with acceptable oral bioavailability, physicochemical and pharmacokinetic properties.