Highly potent anti-inflammatory, analgesic and antioxidant activities of 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thiones

• Published in: Bioorganic & medicinal chemistry letters Vol. 79; p. 129068
• Main Authors: Arshad, Nuzhat, Jawaid, Shumaila, Hashim, Jamshed, Ullah, Irfan, Gul, Somia, Aziz, Aisha, Wadood, Abdul, Khan, Alamzeb
• Format: Journal Article
• Language: English
• Published: England 01.01.2023
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antioxidants - pharmacology; Esters; Molecular Docking Simulation; Thiadiazines - pharmacology; Thiones - pharmacology; Acetic acid writhing model; Analgesic; Ibuprofen; Anti-nociceptive; Indomethacin; Antioxidant; Anti-inflammatory; Molecular docking; Tetrahydro thiadiazine thiones
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.129068

Four series of tetrahydro-2H-1,3,5-thiadiazine-2-thiones (series A and B including two novel enantiopure isomers), tetrahydro-2H-1,3,5-thiadiazine-6-thiones (series C) and N-3 ester derivatives of tetrahydro-2H-1,3,5-thiadiazine-6-thiones (series D) were synthesized and evaluated for their anti-inflammatory, analgesic and anti-oxidant activities. These THTT analogues specially series D were first time examined for their in vitro anti-inflammatory, in vivo analgesic and anti-oxidant activities. Among them lipophilic compounds (series B and D) were found to be highly active for anti-inflammatory evaluation with IC values between 5.1-16.9 and 4.1-32.4 μM, respectively when compared with the standard drug ibuprofen IC  = 11.2 μM. The structure-activity relationship exposed the importance of lipophilic substituents especially ester and n-propyl group for inhibition of inflammation. The molecular docking studies demonstrated that all the active analogues of THTT have notable binding relations with Arg120 of the active sites of COX-1 enzyme either through CS moiety of the THTT nucleus or with COO attached at N-3 of THTT nucleus. In vivo analgesic activity of the selected THTT compounds 14, 17, 18, 19 (series B) and 28 (series D) were also carried out by acetic acid-induced writhing procedure. The compound 28 showed significant anti-nociceptive/analgesic activity at the oral dose of 5 mg/kg body weight with the percent protection (32.05 %) when compared with standard indomethacin at 10 mg/kg (48.83 %). Additionally, these compounds demonstrated the moderate level of antioxidant potential with IC values in the range of 60.9 to 93.6 μM (standard butylated hyroxyanisole; IC  = 44.2 μM). These results indicated that this class of heterocyclic compounds may be a template specially to design better anti-inflammatory and analgesic agents.