ABSTRACT
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.
Subject(s)
Antimalarials/chemical synthesis , Benzimidazoles/chemical synthesis , Pyridines/chemical synthesis , Administration, Oral , Animals , Antimalarials/pharmacokinetics , Antimalarials/pharmacology , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Drug Resistance, Multiple , Humans , In Vitro Techniques , Injections, Intraperitoneal , L Cells , Malaria/drug therapy , Male , Mice , Microsomes, Liver/metabolism , Plasmodium berghei , Plasmodium falciparum/drug effects , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Tris(2-pyridyl)phosphine oxide, (I), C(15)H(12)N(3)OP, is isomorphous with tris(2-pyridyl)phosphine. Because of a combination of C-H.O and C-H.N interactions, the crystal packing is denser in the title compound than in the related compounds triphenylphosphine oxide and tris(2-pyridyl)phosphine.
ABSTRACT
In the crystal structure of 2,2'-bipyridinium(1+) bromide monohydrate, C(10)H(9)N(2)(+).Br(-).H(2)O, the cation has a cisoid conformation with an intramolecular N-H.N hydrogen bond. The cation also forms an N-H.O hydrogen bond to an adjacent water molecule, which in turn forms O-H.Br(-) hydrogen bonds to adjacent Br(-) anions. In this way, a chain is formed extending along the b axis. Additional interactions (C-H.Br(-) and pi-pi) serve to stabilize the structure further.
