Matrix‐Metalloproteinase Inhibitory Study of Novel Tetrahydroisoquinoline‐4‐carboxylates: Design, Synthesis, and Molecular Docking Studies

The design, molecular docking, synthesis and structure‐activity relationship (SAR) of a series of novel methyl 1‐oxo‐2‐(propan‐2‐yl)‐3‐(pyridin‐3‐yl)‐1,2,3,4‐tetrahydroisoquinoline‐4‐carboxylates, were investigated for antiproliferative and cytotoxic studies by screening against cancer cell lines of different origin by MTT, LDH and Trypan Blue Assay. Irrespective of cell lines, among the synthesized nonpeptido‐mimetic analogs 5a–e, 5c has executed potent bio‐potency with IC50 value of 7.00 to 7.21 μM, which further expressed in‐vivo anti‐tumor activity against murine T‐cell lymphoma cell lines (Daltons Lymphoma‐DLA) by regressing tumor growth. The formation of neovessels from the vasculogenesis was diminished reflecting the antitumor activity. The neovessel formation is directly relied on expression of matrix meteloproteases (MMP's) level which was drastically reduced by 5c treatment as evaluated by immonoblot assays. This is further supported by in‐silico ADMET studies performed by ACD I‐Lab 2.0 were in agreement with Lipinski rule of five. Reporting results were assessed as a positive parameter for further validation of the compound for therapeutic potential of cancer by 5c for preclinical studies in near future.