Novel 1,3,4-thiadiazole conjugates derived from protocatechuic acid: Synthesis, antioxidant activity, and computational and electrochemical studies

Abstract

A series of 15 novel 1,3,4-thiadiazole amide derivatives containing a protocatechuic acid moiety were synthesized and structurally characterized. In addition, the corresponding imino (4) and amino (5) analogues of a phenyl-substituted 1,3,4-thiadiazole amide derivative 3a were prepared to compare the effects of the structural changes on the radical-scavenging activity. The obtained compounds were examined for their antioxidative potential by 2,2diphenyl-1-picrylhydrazyl (DPPH) and 2,2 0 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. In addition, selected compounds were studied by density functional theory (DFT) and cyclic voltammetry experiments. The tested compounds showed high potential to scavenging DPPH radical and ABTS radical cation compared with the referent antioxidants ascorbic acid and nordihydroguaiaretic acid (NDGA). On the basis of the calculated thermodynamic parameters, it can be concluded that the sequential proton loss electron transfer (SPLET) mechanism represents the most probable reaction path in a polar solvent for DPPH radicalescavenging activity. On the other hand, the single electron transfer followed by proton transfer (SET-PT) can be a likely mechanistic pathway in the case of an ABTS radical cation.

Free radical scavenging mechanism of 1,3,4-oxadiazole derivatives: thermodynamics of O–H and N–H bond cleavage

“…Also, recall that the more delocalized the spin density in the radical, the easier the radical is formed, the lower the BDE. For MOXM 19, the order of radical spin density delocalization is, MOXM 19 2, the most feasible site for the formation of MOXM 19 radical is at the 17-OH site, while, the least is the 2-NH site. Similarly, the preferred site of radical formation for MOXM 04 and MOXM 31 molecules is the 15-OH site.…”

“…They exist in different isomeric forms such as 1,2,4-, 1,2,5-, 1,2,3-and 1,3,4-oxadiazoles. From recent studies, 1,3,4-oxadiazoles are an important class of heterocyclic compounds with a variety of biological activities such as anticancer [1,2,3,4]; antibacterial [5,6,7]; anti-inflammatory [8,9]; antifungal [10,11,12,13,14] and antioxidant [15,16,17,18,19] activities.…”

“…The reaction Gibbs free energy results computed for each of the molecules MOXM 04, MOXM 19 and MOXM 31 facilitated the prediction of their thermodynamically plausible mechanisms of free radical scavenge. It was observed the HAT and SPLET mechanisms were thermodynamically feasible reaction pathways for MOXM 04, MOXM19 and MOXM 31 at their 15-OH sites in vacuum. For MOXM 19 an additional position with thermodynamic feasibility was observed at 17-OH site.…”

Design, Synthesis, In Silico and In Vitro Studies for New Nitric Oxide-Releasing Indomethacin Derivatives with 1,3,4-Oxadiazole-2-thiol Scaffold

“…Its use offers several advantages: (i) it is an essential part of the pharmacophore, based on its ligand binding role; (ii) it acts as a flat aromatic linker assuring an appropriate molecule orientation; (iii) it induces metabolic stability, water solubility and lower lipophilicity; (iv) it can easily chemically modulate the compounds which contain carbonyl groups such as amides, carbamates, esters and hydoxamic esters [32,50,51]. According to the literature data, the compounds containing the oxadiazole core, generally 1,3,4-oxadiazole motif, have important biological effects such as anti-inflammatory [32,52,53], antioxidant [54,55], antidiabetic [56], anticonvulsant [57], anticancer [58], antitubercular [59,60], antiviral [61], antidepressant [62]. There have already been several approved oxadiazole-based drugs such as: furamizole (strong antibacterial activity, an antibiotic), butalamine (a vasodilator), oxolamine (a cough suppressant), pleconaril (an antiviral), fasiplon (a non-benzodiazepine anxiolitic drug), raltegravir (an antiretroviral drug for the treatment of HIV infection), nesapidil (an anti-arrhythmic drug), zibotentan (an anticancer drug) as well as tiodazosin (an antihypertensive drug) (Figure 1).…”

Synthesis Of 2,5-Dimersapto-1,3,4-Thiadiazol Products

“…New derivatives of 1,3,4-thiadiazole are gaining popularity because they are widely used in various directions [4]. They are used against fungi [5][6][7][8], antibacterial [9-12], antiinflammatory [13][14][15], analgesic [16][17], antileishmaniasis [18][19], anti-cancer [20][21][22], antioxidant [23][24][25][26], molluscicidal [27 -28], antidiabetic [29], central nervous system (CNS) depressant [30], anticonvulsant [31][32], anti-tuberculosis [33][34], anti-depressant [35],…”