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Synthesis and antiviral activity of novel amidino- substituted coumarin-benzazole hybrids

Background Molecular hybridization has been in the focus of medicinal chemists more than two decades. Benzimidazole and benzothizole derivatives as most important benzazole representatives, have been well recognized as one of the most important privileged substructures and structural motifs in medicinal and pharmaceutical chemistry. Amidine substituents at the termini of the molecule seem to contribute significantly to the molecule - possible biological target complex stability through H-bonding and electrostatic interactions. Aims Herein we present the design, synthesis and structural determination of novel substituted coumarin-benzimidazole/benzothiazole hybrids bearing amidino group on the benzazole core. In this work, we have used molecular hybridization approach to design and synthesize targeted amidino substituted coumarin-benzazole hybrids which were evaluated for their antiviral activity in vitro. Methods Target compounds were prepared by conventional reactions of organic syntheses. Benzimidazole- coumarin hybrids were synthesized by cyclocondensation of 4-amidino 1, 2- phenylenediamines with the chosen coumarine based aldehydes in absolute ethanol by using p- benzoquinone as an oxidant. Benzothiazole-coumarin hybrids were synthesized by cyclocondensation in refluxing acetic acid, between 7-(N, N- diethylamino)-2-oxo-2H-chromene-3-carbaldehyde and amidino-substituted benzenethiolates followed by quenching with hydrochloric acid. All newly prepared amidino substituted coumarin-benzazole hybrids were structurally characterized by using 1H and 13C NMR spectroscopy. Newly synthesized compounds were evaluated for their antiviral activity in vitro against used viruses including HCoV, Influenza, RSV, HSV-1, Yellow fewer, Zika, Sindbis. Results Newly prepared benzazole derivatives were substituted at the position 3 on coumarine ring with either benzimidazole/benzothiazole nuclei bearing amidine moiety, as well as on positions 4, 6 and/or position 7 of the coumarine ring. Coumarin-benzimidazole/benzothiazole hybrids were synthesized in moderate reaction yields. Antiviral activity was tested against several viruses and obtained results revealed that the most promising antiviral activity was shown by coumarin-benzimidazole hybrid with unsubstituted amidine group and chlorine at the position 4 (EC50 4.0 – 39.4 µM) and benzimidazole hybrid with hexacyclic amidine group and bromine and chlorine at the positions 6 and 4 (EC50 9.0 – 43.8 µM). 2- imidazolinyl substituted benzimidazole derivative with bromine and chlorine at the positions 6 and 4 showed selective activity against Influenza H1N1. Benzothiazole hybrids were less active in comparison to benzimidazole hybrids. Interestingly, N, N-diethylamino substituted benzimidazole hybrids did not show any antiviral activity. Opposite, among tested benzothiazole derivatives, the most active was N, N-diethylamino substituted derivative bearing hexacyclic amidine group (EC50 20.4 – 75.3 µM), while 2-imidazolinyl substituted derivative showed moderate activity against two viruses. Conclusion All prepared compounds were evaluated on their antiviral activity in vitro. Within this research we have confirmed the strong influence of the substituents placed at the coumarine nuclei as well as the type of the amidine group placed at the benzazole nuceli on the biological activity. The most significant antiviral activity showed coumarin-benzimidazole hybrids with unsubstituted and hexacyclic amidine group on benzazole nuclei. Newly prepared coumarin-benzazole hybrids showed great biological potential representing thus promising scaffold for further design and optimization for developing of promising antiviral agents.

benzimidazoles, benzothiazoles, amidines, antiviral activity

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