Novel 2-Thiouracil-5-Sulfonamide Derivatives: Design, Synthesis, Molecular Docking, and Biological Evaluation as Antioxidants with 15-LOX Inhibition

Abstract

New antioxidant agents are urgently required to combat oxidative stress, which is linked to the emergence of serious diseases. In an effort to discover potent antioxidant agents, a novel series of 2-thiouracil-5-sulfonamides (4–9) were designed and synthesized. In line with this approach, our target new compounds were prepared from methyl ketone derivative 3, which was used as a blocking unit for further synthesis of a novel series of chalcone derivatives 4a–d, thiosemicarbazone derivatives 5a–d, pyridine derivatives 6a–d and 7a–d, bromo acetyl derivative 8, and thiazole derivatives 9a–d. All compounds were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2), lipid peroxidation, and 15-lipoxygenase (15-LOX) inhibition activity. Compounds 5c, 6d, 7d, 9b, 9c, and 9d demonstrated significant RSA in all three techniques in comparison with ascorbic acid and 15-LOX inhibitory effectiveness using quercetin as a standard. Molecular docking of compound 9b endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.

Synthesis of sulfonylamides containing an isoxazole moiety

“…Found, %: С 55. 19 (17), 95 (20), 70 (18), 69 (12), 56 (25). Found, %: С 54.54; Н 4.59; N 10.12; S 7.…”

“…However, they include compounds with different biological activities: hypoglycaemic [1,2], antitumour [3], antiviral [4][5][6][7][8][9], antiepileptic [10], hypotensive [11], antiprotozoal [12], antifungal [13], anticancer [14][15][16], anti-inflammatory [17], diuretic [18], etc. [19][20][21]. Also, sulfonylamides are a convenient and efficient source of nitrogen and are used in the construction of C-N bonds [22].…”

Sintez sul`fonilamidov, soderzhashhix izoksazol`ny`j fragment

“…Традиционно сульфониламиды рассматриваются как антибактериальные агенты, но среди них можно найти соединения с различной биологической активностью, например гипогликемической [1,2], противоопухолевой [3], противовирусной [4][5][6][7][8][9], противоэпилептической [10], гипотензивной [11], антипротозоальной [12], противогрибковой [13], противораковой [14][15][16], противовоспалительной [17], диуретической [18] и др. [19][20][21]. Кроме того, сульфониламиды являются удобным и эффективным источником азота и используются при построении связей С-N [22], а аддукт сульфониламида и витамина С улучшает оптические свойства поливинилового спирта, что делает возможным его использование в производстве оптических устройств [23].…”

Synthesis, Characterization, and Antibacterial Studies of New Cu(II) and Pd(II) Complexes with 6-Methyl-2-Thiouracil and 6-Propyl-2-Thiouracil

“…Recently, Ahmed et al reported new 2-thiouracil-5-sulfonamide derivatives and their biological properties [39].…”