BIOMAT Database Logo BIOMAT Database Logo

Antimalarial pyrido[1,2-a]benzimidazoles. 2011

Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Department of Chemistry, University of Cape Town, Rondebosch, South Africa.

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 (IC(50) = 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.

UI MeSH Term Description Entries
D007274 Injections, Intraperitoneal Forceful administration into the peritoneal cavity of liquid medication, nutrient, or other fluid through a hollow needle piercing the abdominal wall. Intraperitoneal Injections,Injection, Intraperitoneal,Intraperitoneal Injection
D007739 L Cells A cultured line of C3H mouse FIBROBLASTS that do not adhere to one another and do not express CADHERINS. Earle's Strain L Cells,L Cell Line,L Cells (Cell Line),L-Cell Line,L-Cells,L-Cells, Cell Line,L929 Cell Line,L929 Cells,NCTC Clone 929 Cells,NCTC Clone 929 of Strain L Cells,Strain L Cells,Cell Line L-Cell,Cell Line L-Cells,Cell Line, L,Cell Line, L929,Cell Lines, L,Cell, L,Cell, L (Cell Line),Cell, L929,Cell, Strain L,Cells, L,Cells, L (Cell Line),Cells, L929,Cells, Strain L,L Cell,L Cell (Cell Line),L Cell Lines,L Cell, Strain,L Cells, Cell Line,L Cells, Strain,L-Cell,L-Cell Lines,L-Cell, Cell Line,L929 Cell,Strain L Cell
D008288 Malaria A protozoan disease caused in humans by four species of the PLASMODIUM genus: PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PLASMODIUM OVALE; and PLASMODIUM MALARIAE; and transmitted by the bite of an infected female mosquito of the genus ANOPHELES. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high FEVER; SWEATING; shaking CHILLS; and ANEMIA. Malaria in ANIMALS is caused by other species of plasmodia. Marsh Fever,Plasmodium Infections,Remittent Fever,Infections, Plasmodium,Paludism,Fever, Marsh,Fever, Remittent,Infection, Plasmodium,Plasmodium Infection
D008297 Male Males
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D010962 Plasmodium berghei A protozoan parasite of rodents transmitted by the mosquito Anopheles dureni. Plasmodium bergheus,berghei, Plasmodium
D010963 Plasmodium falciparum A species of protozoa that is the causal agent of falciparum malaria (MALARIA, FALCIPARUM). It is most prevalent in the tropics and subtropics. Plasmodium falciparums,falciparums, Plasmodium
D011725 Pyridines Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations

Related Publications

Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Antimalarial Pyrido[1,2-a]benzimidazoles Exert Strong Parasiticidal Effects by Achieving High Cellular Uptake and Suppressing Heme Detoxification.
August 2022, ACS infectious diseases,
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Antioxidative and antiproliferative activities of novel pyrido[1,2-a]benzimidazoles.
February 2017, Molecular diversity,
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Regioselective synthesis of pyrazolo[4,5-g]pyrido[1,2-a]benzimidazoles: cytotoxic derivatives of pyrido[1,2-a]benzimidazolic ring system.
November 1998, Chemical & pharmaceutical bulletin,
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles.
June 1999, Bioorganic & medicinal chemistry letters,
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Intrinsic fluorescence properties of antimalarial pyrido[1,2-a]benzimidazoles facilitate subcellular accumulation and mechanistic studies in the human malaria parasite Plasmodium falciparum.
November 2020, Organic & biomolecular chemistry,
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
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.
February 2017, Journal of medicinal chemistry,
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Benzimidazole condensed ring systems 10 (1). Synthesis and cytotoxic activity of some pyrido[1,2-a]benzimidazoles.
January 1995, Farmaco (Societa chimica italiana : 1989),
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Benzimidazole condensed ring systems. XI. Synthesis of some substituted cycloalkyl pyrido[1,2-a]benzimidazoles with anticipated antineoplastic activity.
January 1999, European journal of medicinal chemistry,
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Rhodium(III)-catalyzed vinylic sp2 C-H bond functionalization: efficient synthesis of pyrido[1,2-α]benzimidazoles and imidazo[1,2-α]pyridines.
September 2013, Organic & biomolecular chemistry,
Albert J Ndakala, and Richard K Gessner, and Patricia W Gitari, and Natasha October, and Karen L White, and Alan Hudson, and Foluke Fakorede, and David M Shackleford, and Marcel Kaiser, and Clive Yeates, and Susan A Charman, and Kelly Chibale
Synthesis and biological evaluation of some novel pyrido[1,2-a]pyrimidin-4-ones as antimalarial agents.
May 2014, European journal of medicinal chemistry,
Copied contents to your clipboard!