Inactivating Activities and Mechanism of Imidazo[1,2- c ]pyrimidin-5(6 H )-one Nucleoside Derivatives Incorporating a Sulfonamide Scaffold.

Twenty-eight imidazo[1,2- c ]pyrimidin-5(6 H )-one nucleoside derivatives incorporating a sulfonamide scaffold with preferable inactivating activities on pepper mild mottle virus (PMMoV) were designed and synthesized. Then, compound B29 with illustrious inactivating activity against PMMoV was received on the basis of the three-dimensional quantitative structure-activity relationship (3D-QSAR) model, with the EC 50 of 11.4 μg/mL, which was superior to ningnanmycin (65.8 μg/mL) and template molecule B16 (15.3 μg/mL). Furthermore, (1) transmission electron microscopy (TEM) indicated that B29 could cause severe fracture of virions; (2) microscale thermophoresis (MST) and molecular docking further demonstrated that B29 had faintish binding affinities with PMMoV CP R62A ( K d = 202.84 μM), PMMoV CP L144A ( K d = 141.57 μM), and PMMoV CP R62A,L144A ( K d = 332.06 μM) compared to PMMoV CP ( K d = 4.76 μM); and (3) western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results of pCB-GFP-PMMoV CP R62A , pCB-GFP-PMMoV CP L144A , and pCB-GFP-PMMoV CP R62A,L144A were consistent with MST and confocal. In brief, the above results indicated that the amino acids at positions 62 and 144 of PMMoV CP might be the key amino acid sites of B29 acted on.