Synthesis and pharmacological activity of aroylmethyl derivatives of tricyclic benzimidazole systems containing hydroxy groups in aroyl radicals

Abstract

The synthesis and pharmacological properties of a series of aroylmethyl derivatives of tricyclic benzimidazole systems containing hydroxy groups in aroyl radicals are described. It is established that most of the synthesized compounds exhibit a high antioxidant activity, possess pronounced hemorheological properties, and influence the blood glucose level.The treatment of various pathological states accompanied by the intensification of peroxidation processes [1 -3] usually involves antioxidants [4 -6]. In continuation of the search for new substances possessing antioxidant properties, we have synthesized a series of aroylmethyl derivatives of 2,3-dihydroimidazo-and 2,3,4,10-tetrahydropyrimido-[1, 2-a]benzimidazoles containing various phenolic substituents in the aroyl radical (II -V) and their open forms, representing 2-hydroxyalkylaminobenzimidazoles with 3,5-ditert-butyl-4-hydroxyphenacyl radical in position 1 (IXa, IXb). The synthesized compounds were characterized with respect to antioxidant properties and some other pharmacological effects on various models involving activation of the free-radical processes (in particular, those influencing blood rheology).Compounds II -V can be obtained by directly introducing acylmethyl groups into tricycles Ia and Ib with the aid of the corresponding substituted phenacylbromides.In contrast to smoothly proceeding reactions of tricycles Ia and Ib with 3,5-di-tert-butyl-4-hydroxyphenacylbromide leading to derivatives IV and V, the reactions with 4-hydroxy-and 3,4-dihydroxyphenacylbromides are rather ambigu-ous. These reactions yield ketones II and III heavily contaminated with resinous products, which can be separated neither by recrystallization nor by column chromatography (because of their low mobility). However, using the saponification of methoxy groups in N-para-methoxyphenacyl derivatives of these heterocycles (described in [7]) and in 4-hydroxy-and 3,4-dihydroxyphenacyl derivatives VI in concentrated NBr, we obtained the target products II and III in a rather pure form and with good yields. The restoration of ketones IV and VI by sodium borohydride in MeOH or EtOH yielded alcohols VII and VIII, respectively. n = 1 (Ia -VIIa), 2 (Ib -VIIb, IXa), 3 (IXb); Ar = C 6 H 4 OH-4 (II); C 6 H 3 (OH) 2 -3,4 (III); 3,5-di-tert-butyl-4-hydroxyphenyl (IV, V*, VIII, IX), C 6 H 3 (OCH 3 ) 2 (VI, VII); * Compound Vb contains Me groups in positions 7 and 8.

Condensed Benzimidazoles Are a Novel Scaffold for Antioxidant Agents’ Search and Development

“…Compounds with 4-and 3-oxyphenyl substitutes or 2,4-and 2,5-dioxyphenyl substitutes, as a rule, laсked 3,4-dioxyphenyl-IMBI in activity; however they were similar in it to BHT [10]. Most of aroylmethyl derivatives of tricyclic benzimidazole systems containing hydroxy groups in aroyl radicals also proved to be highly active antioxidant substances that were superior to dibunol [11]. Derivatives of 9-R-2-halogenophenyl-IMBI had a pronounced inhibitory effect on the processes of lipid peroxidation comparable to dibunol [15].…”

“…Condensed benzimidazole derivatives were synthesized, and experimental screening of the antioxidant activity of new chemical compounds was carried out among the derivatives of 2-(hetaryl) imidazo[1,2-a]benzimidazoles (IMBI) [5], 3-aroyl-and 3-hetaroyl-IMBI [6], 2-methoxyphenyl-substituted 9-dialkylaminoethyl-IMBI [7], 2-methoxy-phenyl-and 2-oxyphenyl-substituted 1-dialkylaminoalkyl-IMBI [8], N-acylmethyl derivatives of 9H-2,3-dihydro-IMBI and 10H-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazoles [9], 9-dialkylaminoethyl-2-oxy(dioxy)phenyl-IMBI [10], aroylmethyl derivatives of tricyclic benzimidazole systems containing hydroxy groups in aroyl radicals [11] [17], amides of 2,3-dihydroimidazo-and 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazolyl-acetic acids [18], phenyl-and alkylthiocarbamides of 2,9-disubstituted IMBI [19], and 1-substituted 2-benzylaminobenzimidazoles with phenyl methoxyls [20]. Butylated hydroxytoluene (BHT, CAS Number 128-37-0), also known as dibunol, was chosen as a comparative drug.…”

Search for compounds with antioxidant and antiradical activity among N9-substituted 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles

“…By chemical nature, antioxidants represent a wide class of compounds: phenols and polyphenols (tocopherols, eugenol, pyrocatechol, gallic acid derivatives), flavonoids (rutin, quercetin), steroid hormones (lecithin, cephalin) and many other compounds (Belviranli and Okudan 2015;Neha et al 2019). In addition, the N 9 -substituted imidazo[1,2-a]benzimidazole derivatives, which we are actively studying, also demonstrate antioxidant properties, which allows us to consider this group of compounds as promising for further modification and development of new antioxidants (Anisimova et al 2007(Anisimova et al , 2016Kosolapov et al 2013;Spasov et al 2017).…”