TY - JOUR
T1 - N-aryl-2-aminobenzimidazoles
T2 - Novel, efficacious, antimalarial lead compounds
AU - Ramachandran, Sreekanth
AU - Hameed P., Shahul
AU - Srivastava, Abhishek
AU - Shanbhag, Gajanan
AU - Morayya, Sapna
AU - Rautela, Nikhil
AU - Awasthy, Disha
AU - Kavanagh, Stefan
AU - Bharath, Sowmya
AU - Reddy, Jitendar
AU - Panduga, Vijender
AU - Prabhakar, K. R.
AU - Saralaya, Ramanatha
AU - Nanduri, Robert
AU - Raichurkar, Anandkumar
AU - Menasinakai, Sreenivasaiah
AU - Achar, Vijayashree
AU - Jiménez-Díaz, María Belén
AU - Martínez, María Santos
AU - Angulo-Barturen, Iñigo
AU - Ferrer, Santiago
AU - Sanz, Laura María
AU - Gamo, Francisco Javier
AU - Duffy, Sandra
AU - Avery, Vicky M.
AU - Waterson, David
AU - Lee, Marcus C.S.
AU - Coburn-Flynn, Olivia
AU - Fidock, David A.
AU - Iyer, Pravin S.
AU - Narayanan, Shridhar
AU - Hosagrahara, Vinayak
AU - Sambandamurthy, Vasan K.
PY - 2014/7/9
Y1 - 2014/7/9
N2 - From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.
AB - From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.
UR - http://www.scopus.com/inward/record.url?scp=84906075395&partnerID=8YFLogxK
U2 - 10.1021/jm500715u
DO - 10.1021/jm500715u
M3 - Article
C2 - 25007124
AN - SCOPUS:84906075395
SN - 0022-2623
VL - 57
SP - 6642
EP - 6652
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 15
ER -
