Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPK mt ) inhibition activity and molecular modelling studies

• Published in: Journal of enzyme inhibition and medicinal chemistry 2024-12, Vol.39 (1), p.2386668
• Main Authors: El-Shoukrofy, Mai S, Atta, Amal, Fahmy, Salwa, Sriram, Dharmarajan, Shehat, Michael G, Labouta, Ibrahim M, Mahran, Mona A
• Format: Article
• Language: English
• Subjects: Animals; antitubercular activity; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Biginelli; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Mice; Microbial Sensitivity Tests; Models, Molecular; molecular dynamics simulation; Molecular Structure; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis thymidine monophosphate kinase; Nucleoside-Phosphate Kinase - antagonists & inhibitors; Nucleoside-Phosphate Kinase - metabolism; RAW 264.7 Cells; Structure-Activity Relationship; Tetrahydropyrimidine
• ISSN: 1475-6366; 1475-6374; 1475-6374
• DOI: 10.1080/14756366.2024.2386668

New Biginelli adducts were rationalised, the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of thymidine monophosphate kinase (TMPK ). Repurposing was one of the design rationale strategies for some selected mimics of the designed compounds. The anti-TB activity was screened against the M H Rv strain where was superior to ethambutol (EMB), and was 9-fold more potent than pyrazinamide (PZA). Additionally, compounds , and elicited higher anti-TB activity than PZA, showing better safety profiles than EMB against RAW 264.7 cells' growth. TMPK inhibition assay released compounds and as the most potent inhibitors. Docking studies presumed the binding modes and molecular dynamics (MD) simulation revealed the dynamic stability of TMPK complex over 100 ns prediction of the chemo-informatics properties of the most active compounds was conducted.