442870-24-8Relevant articles and documents
Antimalarial pyrido[1,2-a]benzimidazoles
Ndakala, Albert J.,Gessner, Richard K.,Gitari, Patricia W.,October, Natasha,White, Karen L.,Hudson, Alan,Fakorede, Foluke,Shackleford, David M.,Kaiser, Marcel,Yeates, Clive,Charman, Susan A.,Chibale, Kelly
, p. 4581 - 4589 (2011)
A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC50 = 0.047 μM v 0.17 μM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.
Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model
Singh, Kawaljit,Okombo, John,Brunschwig, Christel,Ndubi, Ferdinand,Barnard, Linley,Wilkinson, Chad,Njogu, Peter M.,Njoroge, Mathew,Laing, Lizahn,Machado, Marta,Prudêncio, Miguel,Reader, Janette,Botha, Mariette,Nondaba, Sindisiwe,Birkholtz, Lyn-Marie,Lauterbach, Sonja,Churchyard, Alisje,Coetzer, Theresa L.,Burrows, Jeremy N.,Yeates, Clive,Denti, Paolo,Wiesner, Lubbe,Egan, Timothy J.,Wittlin, Sergio,Chibale, Kelly
, p. 1432 - 1448 (2017/03/08)
Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.
