Stereoselective and regioselective Heck arylation at C-17 exocyclic double bond of andrographolide to generate labdane-based lead molecule against acute lung injury

• Published in: Journal of molecular structure 2023-08, Vol.1286, p.135568, Article 135568
• Main Authors: Kumar, Amit, Gour, Abhishek, Dhiman, Sumit, Hudait, Nandagopal, Kumar, Puneet, Vashishth, Deepika, Kaur, Sarabjit, Abdullah, Sheikh Tasduq, Nandi, Utpal, Mukherjee, Debaraj
• Format: Article
• Language: English
• Subjects: Acute lung injury; Andrographolide; Heck arylation; Natural product; Semi-synthetic modification
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2023.135568

•Stereoselective & regioselective Heck arylation reactions at C-17 exocyclic double bond of AG-1.•Series of compound were synthesized (AG-3 to AG-16).•In vivo efficacy of AG-12 and AG-13 in comparison to AG-1 using an LPS-induced acute lung injury model against COVID-19 infection.•AG-13 showed promising action towards reduction of the neutrophil count, minimization of oxidative stress, and inhibition of inflammatory cytokines.•Molecular docking against the target. Andrographolide (AG-1) is identified as an attractive scaffold based on in silico/in vitro/in vivo (preclinical and clinical) studies against COVID-19 infection, for which hardly any effective drug is available to date. Due to complexity of its chemical structure, stereoselective and regioselective Heck arylation reactions at C-17 exocyclic double bond of AG-1 is a major challenge and we stepped forward to generate a small focused library of compounds. Among all the molecules, AG-12 and AG-13 were predicted to have better pharmacokinetic profiles than AG-1. Upon evaluation of in vivo efficacy of AG-12 and AG-13 in comparison to AG-1 using an LPS-induced acute lung injury model, AG-13 showed promising action towards reduction of the neutrophil count, minimization of oxidative stress, and inhibition of inflammatory cytokines. Further, lead optimization should be carried out towards developing potential natural product-driven therapeutics to combat acute respiratory distress syndrome (ARDS) situations during COVID-19. [Display omitted]