Maphupha_2026_RSC.Adv__

The quinazolinone moieties are common in bioactive molecules, and novel variations of these compounds, preferably generated by sustainable methods, are of interest. Incorporating biocatalysis into the synthesis of active pharmaceutical ingredients offers significant advantages, mainly because enzymes have excellent specificity. In this work, we demonstrate the synthesis of flexible amide-containing quinazolin-4(3H)-ones from aminonitriles using a chemoenzymatic approach. We catalysed the hydration of aminonitriles to aminoamides using nitrile hydratase as a whole-cell biocatalyst. Subsequently, the aminoamides were coupled with ester-bearing benzaldehydes via microwave-assisted cyclisation, followed by laccase/DMSO-mediated oxidative aromatisation to afford the corresponding quinazolinone esters. The esters were then hydrolysed to their corresponding acids with immobilised lipase CALB (Novozym 435). Finally, lipase or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) was used to carry out the amidation of the acid products, yielding the desired amide-containing quinazolin-4(3H)-one derivatives in excellent yields.