Discovery of antitubercular potential of trans-3-indoleacrylic acid and its derivatives targeting Mycobacterium tuberculosis: A combined in vitro and in silico investigation.

The persistent global health challenges posed by Mycobacterium tuberculosis (Mtb) underscore the urgent need to identify novel antitubercular agents from natural origin. The objective of this research is to assess the antitubercular potential of phytocompounds from Datura innoxia against Mtb through in vitro and in silico methods. Eleven natural compounds were screened for antitubercular activity. The molecular docking and pharmacokinetic properties of the lead compounds were assessed against 10 protein targets. Additionally, density functional theory (DFT), and molecular dynamics (MD) simulation were conducted to further evaluate the compound's properties. C-1 (trans-3-indoleacrylic acid) exhibited the strongest antitubercular activity against Mtb H37Ra strain, with a minimal inhibitory concentration (MIC) of 3.12 μg/mL and minimal bactericidal concentration (MBC) of 12.5 μg/mL. C-2 (indole-3-lactic acid) demonstrated the best binding affinity (9.571 kcal/mol), followed by C-1 (-7.467 kcal/mol), particularly with protein PknB (PDB ID: 5U94). In silico ADMET and DFT analyses indicated favorable pharmacokinetics of C-2, and MD simulations further confirmed its stability. C-1 (trans-3-indoleacrylic acid) exhibited the best in vitro activity, while C-2 (indole-3-lactic acid) showed the strongest in silico results. Both candidates are promising agents due to their potent efficacy and favorable stability profiles, and can be used alone or in combination with other antitubercular agents.