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

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 HRv 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.