Benzimidazole- and Imidazole-Fused Selenazolium and Selenazinium Selenocyanates: Ionic Organoselenium Compounds with Efficient Peroxide Scavenging Activities

Abstract

Three new classes of ionic organoselenium compounds containing cationic benzimidazolium and imidazolium ring systems with selenocyanates as counterions are described. The cyclization of N,N′-disubstituted benzimidazolium and imidazolium bromides having N-(CH2)2-Br and N-(CH2)3-Br groups in the presence of potassium selenocyanate (KSeCN) led to formation of the corresponding selenazolium selenocyanates (21a, 21b, 22a, and 22b) and selenazinium selenocyanates (21c, 21d, 22c, and 22d). However, the open-chain selenocyanates with additional selenocyanate counterions (21e, 21f, 22e, and 22f) were formed from the N,N′-disubstituted benzimidazolium and imidazolium bromides having N-(CH2)6-Br groups. Mechanistic studies were carried out to understand the feasibility of such cyclization processes in the presence of KSeCN. The compounds were studied further for their potencies to catalytically reduce H2O2 in the presence of thiols. Interestingly, the cyclic selenazolium (21a, 21b, 22a, and 22b) and selenazinium compounds (21c, 21d, 22c, and 22d) exhibited significantly higher antioxidant activities than the corresponding acyclic selenocyanates (21f, 22e, and 22f). Selected compounds (22d and 22e) were further evaluated for their potencies in modulating the intracellular level of reactive oxygen species (ROS) in a representative macrophage cell line (RAW 264.7). Owing to the cationic nature of compounds, they may target and scavenge mitochondrial ROS in the cellular medium.

Benzimidazole-based ionic and non-ionic organoselenium compounds: innovative synthetic strategies, structural characterization and preliminary anti-proliferative activities

“…Column chromatography was performed either with a glass column loaded with neutral alumina or using an automated flash chromatography system (CombiFlash NextGen100, Teledynet) with manually packed cartridges using neutral alumina. NMR spectra ( 1 H, 13 C and 77 Se) were recorded on Bruker (400 or 600 MHz) NMR spectrometers and the chemical shifts were cited with respect to TMS (Me 4 Si) as an internal standard ( 1 H and 13 C nuclei) and Ph 2 Se 2 as an external standard ( 77 Se nuclei). Mass spectrometric analysis was performed using an Agilent Q-TOF 6520 High Resolution Mass Spectrometer in ESI-positive mode analysis.…”

“…Compounds 11a-5 and 9d were synthesized following our reported method. 13 The 1 H, 13 C and 77 Se NMR spectra of the synthesized compounds are included in the ESI † (Fig. S1-S80).…”

“…1 H NMR (DMSO-d 6 , 600 MHz): d (ppm) = 8.03-7.98 (m, 2H), 7.64-7.63 (m, 2H), 7.39 (d, 2H, J = 7.7 Hz), 7.01 (d, 2H, J = 8.2 Hz), 5.63 (s, 2H), 4.54 (t, 2H, J = 5.6 Hz), 3.80 (s, 3H), 3.60 (t, 2H, J = 5.9 Hz), 2.61 (t, 2H, J = 5.9 Hz). 13 Compound 8c. Compound 8c was prepared following GP1 from compound 11c-2 (0.15 g, 0.33 mmol) and KSeCN (0.14 g, 0.99 mmol) in acetonitrile (6 mL).…”

“…A plausible stepwise mechanism for the KSeCN-induced cyclization of 11a-1 and 11a-2 via the generation of NHC (18a-1, 18a-2) is proposed in Scheme 4B. 13 Scheme 1 Synthetic schemes to benzimidazole-based ionic organoselenium compounds 7a-7c and 8a-8c. The reaction of bromides 11a-1 and 11a-2 with 1.0 equiv.…”

“…In 2021, we showed the significantly higher antioxidant activities of ionic heterocyclic selenazolium and selenazinium selenocyanates than the corresponding long chain acyclic organoselenocyanates. 13 Considering the importance of benzimidazole as an active heterocyclic pharmacophore and the significance of key electronic groups such as 4-NO 2 and 4-OMe in the anti-cancer activities of different aromatic compounds in the literature, three different classes of benzimidazole-based ionic (Class-A and Class-B) and non-ionic (Class-C) organoselenium compounds were rationally developed (Fig. 1B).…”