Benzouracil–coumarin–arene conjugates as inhibiting agents for chikungunya virus

• New uracil–coumarin–arene triply conjugated compounds were designed and synthesized.
• Five compounds exhibited inhibitory activity (EC50 = 10.2–19.1 μM) against chikungunya virus in Vero cells.
• Compounds with a scaffold of benzouracil–SCH2–coumarin–OSO2–arene showed the most appealing antiviral results.
• The potency was affected by the nature of uracil, the joint between the units, and the substituent on the arene.

Chikungunya virus (CHIKV) is an arbovirus that was first recognized in an epidemic form in East Africa in 1952–1953. The virus is primarily transmitted through mosquitoes and the resulting disease, chikungunya fever, is found in nearly 40 countries. Neither an effective vaccine nor a specific antiviral drug exists for treatments of chikungunya fever. Thus 22 new conjugated compounds of uracil–coumarin–arene were designed and synthesized as potential inhibiting agents. Their chemical structures were determined unambiguously by spectroscopic methods, including single-crystal X-ray diffraction crystallography. The three units in these conjugates were connected by specially designed –SCH2– and –OSO2– joints. Five of these new conjugates were found to inhibit CHIKV in Vero cells with significant potency (EC50 = 10.2–19.1 μM) and showed low toxicity (CC50 = 75.2–178 μM). The selective index values were 8.8–11.5 for three conjugates. By analysis of the data from the anti-viral assays, the structure–activity relationship is derived on the basis of the nature of the uracil, the functional groups attached to the arene, and the joints between the ring units.

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