Abstract
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.
Highlights
Dengue fever is a rapidly spreading mosquito-borne viral illness affecting human populations in tropical and subtropical regions
According to thin-layer chromatography analysis, the majority of the newly formed compound was located at a retardation factor (Rf) value (Rf = 0.8, hexane:ethyl acetate, 70:30) that was not expected for the desired compound (3a, expected Rf between 0.1–0.3)
Isolation via column chromatography of the newly formed compound followed by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis, as discussed below, indicated that the desired dimeric adamantane compound
Summary
Dengue fever is a rapidly spreading mosquito-borne viral illness affecting human populations in tropical and subtropical regions. There has been an increase in the incidence of the disease, from nine dengue-reporting countries in the 1950’s to a current public health concern in over 100 countries [1]. The dengue virus (DENV) exists as four closely related serotypes, DENV1, DENV2, DENV3, and DENV4. Worldwide more than 390 million people become infected with the DENV each year, with approximately 20,000 deaths [1]. The lack of an effective vaccine or approved chemotherapeutic agent for the dengue disease has prompted urgent investigations into these areas to enable adequate prevention and treatment. Given the growing global burden that is imposed by the DENV, intensified efforts to investigate new effective scaffolds as potential inhibitors of the DENV are warranted
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