Design and Synthesis of Quinoline-Pyrazine Based Carboxamides: Leukemic Cancer Active Ugi Adducts

The design and synthesis of new chemical entities (NCEs) with suitable physicochemical properties are playing a key role in medicinal research areas. Hence, we have designed and synthesized the 10 diverse scaffolds by rightly selecting the quinoline and pyrazine to articulate carboxamide derivatives in a single-step process with maximum conversation in a shorter time through diverse studies of Ugi multi-component reaction. Molecular docking studies against FMS-like tyrosine kinase-3 (FLT3) provided well-clustered solutions for the binding modes of these molecules and shed light on the key structural features governing the binding affinity. Two carboxamides derivatives with 3,4,5-trimethoxy, and chloro substituents showed comparable potency in Leukemia cell lines and medium efficacy in Breast and Melanoma cancer. These results suggest that pyrazine and quinoline-based carboxamides may be prominent as new anti-cancer agents in chemotherapy. Additionally, in silico analysis was employed to predict the comprehensive physicochemical ADME profile (absorption, distribution, metabolism, and excretion) of the carboxamide derivatives which was proven drug-like properties. A novel adducts articulated by Ugi-4-CC reaction was developed by clubbing of four fragments i. e., quinoline-3-amine, pyrazine-2-carboxylic acid, aldehyde and tertiary butyl isocyanide. In vitro anti-cancer study in NCI-60 cell-lines directed the ortho position with chloro and trimethoxy (at 3,4,5-position) in aldehydic fragments could serve as potent motif and which was mechanized by in silico screening using FMS-like tyrosine kinase 3 (FLT3) (PDB code: 4rt7). image