Synthesis, Structure, and Neuroprotective Properties of Novel Imidazolyl Nitrones

Abstract

A new series of imidazolyl nitrones spin traps has been synthesized and evaluated pharmacologically. The salient structural feature of these molecules is the presence of an imidazole moiety substituted by aromatic or heteroaromatic cycles. This connectivity imparts to the nitrone superior neuroprotective properties in vivo and in parallel reduced side effects and toxicity. Thus compound 6a (a 2-phenylimidazolyl nitrone) administered intraperitoneally protects (80%) mice from lethality induced by an intracerebroventricular administration of tert-butyl hydroperoxide (t-BHP) an oxidant capable of inducing neurodegenerative processes. Administration of the archetypal nitrone phenyl-tert-butyl nitrone (PBN) at an equimolar dose also affords some protection (60%) in this test. However, this activity is accompanied by hypothermia, whereas no such effect is apparent for 6a. Moreover, previously prepared nonsubstituted or alkyl-substituted imidazolyl nitrones were shown to be extremely toxic to rats in contrast to the compounds prepared in this study. The observed activities in vivo correlate well with the calculated partition coefficients (ClogP) and HOMO energy level.

Monocyclic, Substituted Imidazoles as Glycosidase Inhibitors

“…Formylation of 21a, 21b, and 21c was similar to the one of 15, providing 22a, 22b, and 22c [25] (66 ± 75%) that were reduced to the methanols 23a, 23b, and 23c (66 ± 75%), respectively. Detritylation with AcOH in MeOH gave the disubstituted, N-unprotected imidazoles 24a (91%), 24b [26] [27] (83%), and 24c (54%), respectively.…”

“…), 3167m, 3065m, 3007s, 2924m, 2862m, 1960w, 1909w, 1818w, 1733w, 1597m, 1574m, 1493s, 1448s, 1370s, 1283m, 1155m, 1087m, 1039s, 1017m, 1002m, 3500 ± 2500s, 1598m, 1505m, 1464s, 1390m, 1350w, 1288w, 1233m, 1146m, 1038s, 1026s, 988s, 858m, 4-Phenyl-1-(triphenylmethyl)-1H-imidazole (21c) [23] [24]. Prepared according to [25]. R f (hexane/AcOEt 1 : 1) 0.59.…”

“…M.p. 1848 (EtOH; [25]: 1878). IR (CHCl 3 ): 3158w, 3064w, 2899w, 2844w, 1960w, 1815w, 1699s, 1605w, 1492s, 1461s, 1446s, 1426m, 1395m, 1354m, 1274m, 1167w, 1153m, 1103m, 1087w, 1035w, 950m, 904w, 892w.…”

Microwave‐Assisted 1,3‐Dipolar Cycloaddition: an Eco‐Friendly Approach to Five‐Membered Heterocycles

“…On the other hand, though, one of the most intensely studied of these compounds is α-phenyl-N-tertbutylnitrone, due to its recognized neuroprotective properties. [15][16][17] Nitrones can be synthesized directly from the corresponding nitro compounds by in situ reduction with Zn/ NH 4 Cl in the presence of an aldehyde, followed by acidification. Alternatively, the synthesis of nitrones can involve a two-step procedure in which the hydroxylamine obtained by reduction of a nitro compound is isolated and later treated with an aldehyde.…”

Discovery of New Imidazole Derivatives Containing the 2,4-Dienone Motif with Broad-Spectrum Antifungal and Antibacterial Activity

“…As reported, imidazole rings are widely employed as spin-trapping species in the interesting application of designing drugs with neuroprotective activity [10,11]. These imidazole-based derivatives also have several favorable properties such as excellent bioavailability, good tissue penetrability and permeability and a relatively low incidence of adverse and toxic effects, which suggests that they have considerable development potential in chemistry, materials science and medicinal chemistry [12].…”