Dengue fever is a major public health concern in many tropical and sub-tropical regions. The development of agents that are able to inhibit the dengue virus (DENV) is therefore of utmost importance. This study focused on the synthesis of dual acting hybrids comprising structural features of known DENV inhibitors, amantadine (1) and benzsulfonamide derivatives. Hybrid compound 3, N-(adamantan-1-yl)-4-[(adamantan-1-yl)sulfamoyl]benzamide, was synthesized by reacting amantadine (1) with 4-(chlorosulfonyl)benzoic acid (2), after optimization, in a 2:1 ratio under microwave irradiation conditions in a one-pot reaction. Mono-adamantane derivatives 6 and 7 were synthesised via acyl halide formation of benzoic acid (4) and 4-sulfamoyl benzoic acid (5), respectively, followed by conjugation with amantadine (1) through a conventional or microwave irradiation assisted nucleophilic addition/substitution reaction. The use of microwave irradiation lead to significant increases in yields and a reduction in reaction times. Nuclear magnetic resonance, infra-red and mass spectral data confirmed the structures. Compound 3 and 7 showed significant anti-DENV serotype 2 activity (IC50 = 22.2 µM and 42.8 µM) and low cytotoxicity (CC50 < 100 µM). Possible mechanisms of action are also proposed, which are based on the biological results and molecular docking studies.
Keywords: amantadine; anti-dengue virus serotype 2 activity; cytotoxicity; docking; microwave irradiation; sulfonamide.