β‐Cyclodexrin Mediated Sonochemical Synthesis of 7‐Amino Pyrazolo[1,5‐ a ]Pyrimidine Derivatives in Aqueous Media as Potential Inhibitors of TNF‐α

ABSTRACT An eco‐friendly, metal‐free C‐7 amination of pyrazolo[1,5‐ a ]pyrimidines has been achieved in aqueous media under ultrasound irradiation. A variety of 7‐amino pyrazolo[1,5‐ a ]pyrimidines was prepared by employing this operationally simple method in good yield. The methodology involved reaction of 7‐chloro pyrazolo[1,5‐ a ]pyrimidines with amines using β‐cyclodexrin as a recyclable catalyst. The in silico docking of synthesized compounds into tumor necrosis factor‐α (TNF‐α) suggested TYR135, TYR227, ILE231, LEU133, LEU233, and LEU196 as the common interacting residues of TNF‐α trimer, whereas compounds 3a, 3b, 3d , and 3e showed superior binding affinities with the order 3d > 3a > 3b > 3e . Apart from H‐bonding with B: TYR195, the compound 3d participated in additional H‐bond interactions with B: GLY198 and B: ILE134 through its fluoro group that contributed to its higher binding affinity. Correlating the outcome of in silico studies, the in vitro assay results identified 3a , 3b , and 3d as initial hits with IC 50 in the range of ∼6.1–6.9 µM that were better than known inhibitor thalidomide (but not rolipram). The structure–activity relationship (SAR) analysis within the current series indicated that the 7‐amino aryl moiety played a key role in the observed TNF‐α inhibitory activities. All these studies indicated medicinal value of hits identified and that 3d could be of further interest.