6297-14-9Relevant articles and documents
Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and in Vivo Oral Efficacy Studies
Dziwornu, Godwin Akpeko,Coertzen, Dina,Leshabane, Meta,Korkor, Constance M.,Cloete, Cleavon K.,Njoroge, Mathew,Gibhard, Liezl,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Wittlin, Sergio,Birkholtz, Lyn-Marie,Chibale, Kelly
supporting information, p. 5198 - 5215 (2021/05/06)
A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.
Discovery of a potent non-oxime reactivator of nerve agent inhibited human acetylcholinesterase
de Koning, Martijn Constantijn,Horn, Gabriele,Worek, Franz,van Grol, Marco
, p. 151 - 160 (2018/08/10)
Organophosphorous (OP) compounds (such as nerve agents) inhibit the enzyme acetylcholinesterase (AChE) by covalent phosphylation of a key serine residue in the active site of the enzyme resulting in severe symptoms and ultimately death. OP intoxications are currently treated by administration of certain oxime compounds. The presently fielded oximes reactivate OP-inhibited AChE by liberating the phosphylated serine. Recent research towards new reactivators was predominantly devoted to design, synthesis and evaluation of new oxime-based compounds dedicated to overcoming some of the major limitations such as their intrinsic toxicity, their permanent charge which thwarts penetration of brain tissues and their inability to effectively reactivate all types of nerve agent inhibited AChEs. However, in over six decades of research only limited success has been achieved, indicating that there is a need for alternative classes of compounds that could reactivate OP-inhibited AChE. Recently, a number of non-oxime compounds was discovered in which the 4-amino-2-((diethylamino)methyl)phenol (ADOC) motif proved to be able to reactivate OP-inhibited AChE to some extent. In this paper several structural derivatives of ADOC were synthesized and screened for their ability to reactivate human AChE (hAChE) inhibited by the nerve agents VX, sarin, tabun, cyclosarin and paraoxon. We here disclose that one of those compounds showed a remarkable ability to reactivate OP-inhibited hAChE in vitro and that it is the most potent non-oxime reported to date.
Anti-malaria active 10-H-indolo[3,2-b]quinoline-11-yl-amines. Part 1: Phenol-Mannich-bases of the amodiaquine and cycloquine type
Gorlitzer,Stockmann,Walter
, p. 231 - 235 (2007/10/02)
The 11-chloro-quindoline derivatives 3 react with 4-aminophenol and the mono- and bis-phenol-Mannich-bases 6 to yield the 10 H-indolo[3,2-b]quinoline-11-ylamines 4 and 7. The amodiaquine analogue 7a as the best of all compounds shows a comparable activity with choroquine and inhibits a multiresistant Plasmodium falciparum strain at the same concentration. Compound 7e from the cycloquine-type was selected for an in vivo antitumor screening programme.
