Abstract
In order to identify potential therapeutic inhibitor leads against staphylococcal thioredoxin reductase (SaTrxR), a pivotal anti-staphylococcal drug target protein, a multipronged strategy composed of structure-guided drug discovery empowered by synthetic chemistry approaches has been undertaken. In this context, we conducted an efficient, environmentally benign, β-cyclodextrin-catalyzed synthesis of a fascinating class of angularly fused indeno-pyrido-[2,3-d]-pyrimidines via Knoevenagel condensation and Michael addition reactions of 6-amino uracil and 1,3-indanedione with different kinds of aryl/heteroaryl-substituted aldehydes, in aqueous conditions. All of the reactions proceeded efficiently using aqueous supramolecular β-cyclodextrin as an environmentally friendly solvent system, which was reused up to three cycles. The synthesized fused indeno-pyrido-[2,3-d]-pyrimidines inhibit SaTrxR in silico at low to medium micromolar (μM) concentrations. The in silico results were also supported by in vitro-based agar well diffusion assays, followed by ascertainment of the minimum inhibitory concentration of the top three anti-staphylococcal compounds. The plausible structure-based SaTrxR inhibition mechanism, along with in silico ADMET profiling of the synthesized fused indeno-pyrido-[2,3-d]-pyrimidines has been presented herein. Additionally, DFT calculations were performed to unravel reactive sites and other molecular interactions.