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Elucidating the Structure-Activity Relationships of the Vasorelaxation and Antioxidation Properties of Thionicotinic Acid Derivatives
Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand
Department of Pharmacology, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
Department of Clinical Microbiology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
Chulabhorn Research Institute and Chulabhorn Graduate Institute, Bangkok 10210, Thailand
* Authors to whom correspondence should be addressed.
Received: 11 November 2009; in revised form: 29 December 2009 / Accepted: 4 January 2010 / Published: 6 January 2010
Abstract: Nicotinic acid, known as vitamin B3, is an effective lipid lowering drug and intense cutaneous vasodilator. This study reports the effect of 2-(1-adamantylthio)nicotinic acid (6) and its amide 7 and nitrile analog 8 on phenylephrine-induced contraction of rat thoracic aorta as well as antioxidative activity. It was found that the tested thionicotinic acid analogs 6-8 exerted maximal vasorelaxation in a dose-dependent manner, but their effects were less than acetylcholine (ACh)-induced nitric oxide (NO) vasorelaxation. The vasorelaxations were reduced, apparently, in both NG-nitro-L-arginine methyl ester (L-NAME) and indomethacin (INDO). Synergistic effects were observed in the presence of L-NAME plus INDO, leading to loss of vasorelaxation of both the ACh and the tested nicotinic acids. Complete loss of the vasorelaxation was noted under removal of endothelial cells. This infers that the vasorelaxations are mediated partially by endothelium-induced NO and prostacyclin. The thionicotinic acid analogs all exhibited antioxidant properties in both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide dismutase (SOD) assays. Significantly, the thionicotinic acid 6 is the most potent vasorelaxant with ED50 of 21.3 nM and is the most potent antioxidant (as discerned from DPPH assay). Molecular modeling was also used to provide mechanistic insights into the vasorelaxant and antioxidative activities. The findings reveal that the thionicotinic acid analogs are a novel class of vasorelaxant and antioxidant compounds which have potential to be further developed as promising therapeutics.
Keywords: 1-adamantylthionicotinic acid and derivatives; vasorelaxants; antioxidants; nitric oxide; prostacyclin; molecular modeling
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Prachayasittikul, S.; Wongsawatkul, O.; Worachartcheewan, A.; Nantasenamat, C.; Ruchirawat, S.; Prachayasittikul, V. Elucidating the Structure-Activity Relationships of the Vasorelaxation and Antioxidation Properties of Thionicotinic Acid Derivatives. Molecules 2010, 15, 198-214.
Prachayasittikul S, Wongsawatkul O, Worachartcheewan A, Nantasenamat C, Ruchirawat S, Prachayasittikul V. Elucidating the Structure-Activity Relationships of the Vasorelaxation and Antioxidation Properties of Thionicotinic Acid Derivatives. Molecules. 2010; 15(1):198-214.
Prachayasittikul, Supaluk; Wongsawatkul, Orapin; Worachartcheewan, Apilak; Nantasenamat, Chanin; Ruchirawat, Somsak; Prachayasittikul, Virapong. 2010. "Elucidating the Structure-Activity Relationships of the Vasorelaxation and Antioxidation Properties of Thionicotinic Acid Derivatives." Molecules 15, no. 1: 198-214.