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[Display omitted] • Green and efficient one-pot three-component synthesis of novel drug-like furo[2,3- d ]pyrimidines. • Computer-aided drug design (CADD) approaches for combat COVID-19. • Novel non-covalent inhibitors of the active site and putative allosteric hotspots modulators of both SARS-CoV-2 MPro and PLPro. • Potential COVID-19 drug candidates. • Molecular docking and in silico ADMET studies. • Molecular docking (protein‒ligand) studies on the human body temperature-dependent MPro protein contain zincII (ZnII) ion between His41/Cys145 catalytic dyad in the active site. In this paper, an environmentally benign, convenient, and efficient one-pot three-component reaction has been developed for the regioselective synthesis of novel 5-aroyl(or heteroaroyl)-6-(alkylamino)-1,3-dimethylfuro[2,3- d ]pyrimidine-2,4(1 H ,3 H)-diones (4a‒n) through the sequential condensation of aryl(or heteroaryl)glyoxal monohydrates (1a‒g), 1,3-dimethylbarbituric acid (2), and alkyl(viz. cyclohexyl or tert -butyl)isocyanides (3a or 3b) catalyzed by ultra-low loading ZrOCl 2 •8H 2 O (just 2 mol%) in water at 50 ˚C. After synthesis and characterization of the mentioned furo[2,3- d ]pyrimidines (4a‒n), their multi-targeting inhibitory properties were investigated against the active site and putative allosteric hotspots of both SARS-CoV-2 main protease (MPro) and papain-like protease (PLPro) based on molecular docking studies and compare the attained results with various medicinal compounds which approximately in three past years were used, introduced, and or repurposed to fight against COVID-19. Furthermore, drug-likeness properties of the mentioned small heterocyclic frameworks (4a‒n) have been explored using in silico ADMET analyses. Interestingly, the molecular docking studies and ADMET-related data revealed that the novel series of furo[2,3- d ]pyrimidines (4a‒n), especially 5-(3,4-methylendioxybenzoyl)-6-(cyclohexylamino)-1,3-dimethylfuro[2,3- d ]pyrimidine-2,4(1 H ,3 H)-dione (4g) as hit one is potential COVID-19 drug candidate, can subject to further in vitro and in vivo studies. It is worthwhile to note that the protein–ligand-type molecular docking studies on the human body temperature-dependent MPro protein that surprisingly contains zincII (ZnII) ion between His41/Cys145 catalytic dyad in the active site, which undoubtedly can make new plans for designing novel SARS-CoV-2 MPro inhibitors, is performed for the first time in this paper, to the best of our knowledge. [ABSTRACT FROM AUTHOR]