Supramolecular Efficient Catalysis for Multicomponent Synthesis of Fused Indeno-pyrido[2,3-<i>d</i>]pyrimidines as <i>Staphylococcal Thioredoxin Reductase</i> (<i>Sa</i>TrxR) Inhibitor Leads

In order to identify potential therapeutic inhibitor leads against staphylococcal thioredoxin reductase (<i>Sa</i>TrxR), 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-<i>d</i>]-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-<i>d</i>]-pyrimidines inhibit <i>Sa</i>TrxR <i>in silico</i> at low to medium micromolar (μM) concentrations. The <i>in silico</i> results were also supported by <i>in vitro</i>-based agar well diffusion assays, followed by ascertainment of the minimum inhibitory concentration of the top three anti-staphylococcal compounds. The plausible structure-based <i>Sa</i>TrxR inhibition mechanism, along with <i>in silico</i> ADMET profiling of the synthesized fused indeno-pyrido-[2,3-<i>d</i>]-pyrimidines has been presented herein. Additionally, DFT calculations were performed to unravel reactive sites and other molecular interactions.