Elucidating the Structure-Activity Relationships of the Vasorelaxation and Antioxidation Properties of Thionicotinic Acid Derivatives

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.

Molecular Docking of Aromatase Inhibitors

“…This opens up a plethora of opportunities by enabling the understanding of the molecular basis for the specificity of the aromatase enzyme and its unique catalytic mechanism, which is imperative for the development of the next-generation of AIs. Computational chemistry and relevant molecular simulation approaches have been successfully employed for studying the chemical reactions and binding mechanisms of a wide range of biological and chemical systems [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. As such, in silico tools such as molecular docking are important for shedding light on the binding modalities and interaction strengths of AIs.…”

Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti‐Hyperlipidemic and Antioxidant Agents

“…Also mild antioxidant capacities of different nicotinic acid derivatives, namely thionicotinic acid, thioamide, and thionitrile, were reported , with thionicotinic acid showing the most potent antioxidant radical scavenging activity (33.20%) while the other two compounds exerted almost no activities .…”

Nicotinic acid and derivatives as multifunctional pharmacophores for medical applications

“…Inversely, the most active (SOD activity) compound 10 had the highest µ value. This is due to the electron withdrawing effect of CN group of 10 giving rise to the asymmetric distribution of charges in the molecule [100].…”

“…17) were documented as a novel class of vasorelaxant and antioxidant compounds [100]. Thionicotinic acid (8) exerted the most potent vasorelaxant and antioxidant (DPPH) activities.…”

“…The vasorelaxant effect was partially mediated via endothelium producing nitric oxide (NO) and prostaglandin (PGI 2 ). Molecular modeling study provided mechanistic insight into the vasorelaxant and antioxidant activities [100]. The molecular descriptors account for vasorelaxant activity are the energy gap of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO).…”