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Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their β-adrenoceptor blocking property

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Abstract

The design, synthesis, antinociceptive and β-adrenoceptor blocking activities of several eugenyloxy propanol azole derivatives have been described. In this synthesis, the reaction of eugenol with epichlorohydrin provided adducts 3 and 4 which were N-alkylated by diverse azoles to obtain the eugenyloxy propanol azole analogues in good yields. Adducts 3 and 4 were also reacted with azide ion to obtain the corresponding azide 6. The ‘Click’ Huisgen cycloaddition reaction of 6 with diverse alkynes afforded the title compounds in good yields. The synthesized eugenyloxy propanol azole derivatives were in vivo studied for the acute antinociception on male Spargue Dawley rats using tail-flick test. Compounds 5f, 5g, 7b and 11a exhibited potent analgesic properties in comparison with eugenol as a standard drug. In addition, all compounds were ex vivo tested for β-adrenoceptor blocking properties on isolated left atrium of male rats which exhibited partial antagonist or agonist behaviour compared to the standard drugs. The molecular docking study on the binding site of transient receptor potential vanilloid subtype 1 (TRPV1) has indicated that like capsaicin, eugenyloxy propanol azole analogues exhibited the strong affinity to bind at site of TPRV1 in a “tail-up, head-down” conformation and the presence of triazolyl moieties has played undeniable role in durable binding of these ligands to TRPV1. The in silico pharmacokinetic profile, drug likeness and toxicity predictions carried out for all compounds determined that 5g can be considered as potential antinociceptive drug candidate for future research.

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Acknowledgements

The authors wish to thank Shiraz University of Technology research council for partial support of this work. The authors are thankful from the High Performance Computing research laboratory of Institute for Research in Fundamental Sciences (IPM).

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  1. Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz, 71555-313, Iran

    Somayeh Behrouz, Mohammad Navid Soltani Rad, Bahareh Taghavi Shahraki & Marzieh Behrouz

  2. Faculty of Pharmacy, Shiraz University of Medical Science, Medicinal and Natural Products Chemistry Research Center, P.O.Box 71345-1149, Shiraz, Iran

    Mohammad Fathalipour & Hossein Mirkhani

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  1. Somayeh Behrouz
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Behrouz, S., Soltani Rad, M.N., Taghavi Shahraki, B. et al. Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their β-adrenoceptor blocking property. Mol Divers 23, 147–164 (2019). https://doi.org/10.1007/s11030-018-9867-7

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