Ultrasound assisted regioselective synthesis of novel adamantyl-pyrazolo[1,5-a]pyrimidines in aqueous media and molecular docking and drug likeness studies.

• US assisted synthesis of novel adamantane-pyrazolo[1,5- a ]pyrimidine hybrids. • Crystal analysis of adamantane-pyrazolo[1,5- a ]pyrimidine hybrid 14c. • Docking analysis of the hybrids against target 3CLpro of SARS-CoV-2. • Drug-likeness analysis of the hybrids using Swiss ADME. Multi-step synthesis of adamantyl-pyrazolo[1,5- a ]pyrimidine derivatives under ultrasound irradiation has been described adopting the technique of molecular hybridization, whereby two core bioactive units- adamantanamine and pyrazolo[1,5- a ]pyrimidine templates have been brought together into a new chemical entity. Ultrasound irradiation of N -(adamantan-1-yl)-3-amino- 1H -pyrazole-4-carboxamide with formylated active proton compounds yields the desired hybrids in good to excellent yields. The N -(adamantan-1-yl)-3-amino pyrazolo[1,5- a ]pyrimidine carboxamide derivatives were successfully identified with the help of spectral and analytical data. X-ray crystallography of ethyl 3-(adamantan-1-ylcarbamoyl)-7-methylpyrazolo[1,5- a ]pyrimidine-6-carboxylate (14c) unambiguously confirmed the formation of the desired hybrid. The results and the findings of the docking scores indicate that the active ligands 7a and 11b exhibited highest binding energies with a score of –7.33 Kcal/mol and – 8.73 Kcal/mol, respectively. The inhibition constant (KI) for ligands 7a and 11b were found to be 4.24 µM and 396.32 µM, respectively which are comparatively lower than the control favipiravir thereby conforming to the drug-likeness prediction. These compounds as such become favorable for screening as drug candidates compared to the control favipiravir with lower binding energy, lower lipophilicity range and very high KI constant. The active ligands have promising functions to inhibit and interfere with the replication and maturation of Chymotrypsin-like protease (3CLpro) of SARS-Coronavirus 2. The lower KI, high binding energy and drug-likeness efficiency of the compounds can be further developed into a potent drug molecule against the uncontrollable SARS-COV-2. [Display omitted] [ABSTRACT FROM AUTHOR]