In Silico and In vitro Investigations of Novel CyclopentadPyrimidine Derivatives against Gram-positive, Gram-negative, fungal pathogenic strains, and Mycobacterium tuberculosis

• The synthesised work is performed based on CyclopentadPyrimidines. • Designed 16 compounds were introduced into molecular modelling to pick lead moieties • Synthesized Compounds were evaluated for their in vitro efficacy against microbial strains, and MTB. • The results displayed compounds 2a15, 2a6, 2a13, 2a14, and 2a17 demonstrated notable microbial and TB activities. A novel cyclopentadpyrimidine 2a1-2a25 series was designed and synthesized, which were subsequently assessed for their in vitro antibacterial, antifungal, and antiTB properties. All 16 derivatives were subjected to in silico modelling, molecular dynamics, and ADMET screening to select a lead moiety for synthesis. Molecular docking identified compound 2a13 as the lead molecule with a high binding affinity toward InhA (docking score: −11.4 kcal/mol ), supported by stable molecular dynamics behavior. The antibacterial and antifungal properties of the compounds were assessed using the paper disk diffusion method. Additionally, the compound 2a13 MIC values of 12.4 μg/mL for Gram-positive bacteria, and 2a13 exhibited excellent activity against Gram-negative bacteria (MIC of 14.9 μg/mL). Antifungal activity was highest with 2a13, showing MICs of 13.1 μg/mL against Candida albicans . Furthermore, the potency of the compounds against the Mycobacterium tuberculosis ( MTBH37Rv ) strain was evaluated by the MABA screening method. Out of the 2a15, 2a6, 2a13, 2a14, and 2a17 derivatives examined, most compounds exhibited potent activity against microbial strains and the MTBH37Rv strain. The compounds containing a benzylidene ring, heteroaromatic nature, electron-withdrawing properties, substitution of donating groups, and positioning function have been demonstrated. A unique correlation was identified between minimum inhibitory concentration (MIC) profiles and the position and substitution of antibacterial and anti-TB activity outcomes. The study's findings indicate that the compounds 2a15, 2a6, 2a13, 2a14, and 2a17 exhibited the highest significance level and hold potential as a viable template for treating MTB.