db-820 and Disease-Models--Animal

Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2 ΔTm values greater than pentamidine, IC50 values: T. b. r. (4.8-37nM) and P. f. (10-52nM). Most diamidines and prodrugs gave cures for STIB900 model (11, 19a and 24b 4/4 cures); 12 3/4 cures for GVR35 model. Metabolic stability half-life values for O-methylamidoxime prodrugs did not correlate with STIB900 results.

Topics: Animals; Antiprotozoal Agents; Aza Compounds; Cations; Cell Line; Cell Survival; Disease Models, Animal; Mice; Myoblasts; Parasitic Sensitivity Tests; Pentamidine; Plasmodium falciparum; Poly dA-dT; Prodrugs; Pyrazines; Rats; Structure-Activity Relationship; Transition Temperature; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

Seven novel diamidino 2,5-bis(aryl)thiazoles (5a-g) were synthesized and evaluated against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f.). The diamidines were obtained directly from the corresponding bis-nitriles (4a-g) by the action of lithium bis(trimethylsilyl)amide. The bis-nitriles 4a-f were synthesized in four steps starting with the Stille coupling of 2-tributyltinthiazole with the appropriate cyanoaryl halide. The bis-nitrile 5g was obtained by the palladium facilitated coupling of the mixed tin-silyl reagent 2-trimethylsilyl-5-trimethyltinthiazole with 2-bromo-5-cyanopyridine. The amidoxime potential prodrugs 6a-e, 6g were obtained by the reaction of hydroxylamine with the bis-nitriles. O-Methylation of the amidoximes gave the corresponding N-methoxyamidines 7a-c, 7e, 7g. The diamidines showed strong DNA binding affinity as reflected by DeltaT(m) measurements. Four of the diamidines 5a, 5b, 5d and 5e were highly active in vitro against P. f. giving IC(50) values between 1.1 and 2.5nM. The same four diamidines showed IC(50) values between 4 and 6nM against T. b. r. The selectivity indices ranged from 233 to 9175. One diamidine 5a produced one of four cures at an ip dose of 4x5mg/kg in the STIB900 mouse model for acute African trypanosomiasis. The amidoxime and N-methoxyamidine of 5a were the only produgs to provide cures (1/4 cures) in the same mouse model on oral dosage at 4x25mg/kg.

Topics: Administration, Oral; Animals; Antimalarials; Antiprotozoal Agents; Disease Models, Animal; DNA, Protozoan; Drug Stability; Malaria, Falciparum; Mice; Parasitic Sensitivity Tests; Pentamidine; Plasmodium falciparum; Rats; Stereoisomerism; Structure-Activity Relationship; Thiazoles; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

Surra is an animal pathogenic protozoan infection, caused by Trypanosoma evansi, that develops into a fatal wasting disease. Control measures rely on diagnosis and treatment. However, with the continuous emergence of drug resistance, this tactic is failing, and the pressing need for new chemotherapeutic agents is becoming critical. With the introduction of novel aromatic diamidines, a new category of antitrypanosomal drugs was discovered. Nevertheless, their efficacy within a T. evansi-infected mouse model was not known. In total, 30 compounds previously selected based on their in vitro activity were tested in a T. evansi mouse model of infection. Six of the compounds were capable of curing T. evansi-infected mice at drug doses as low as 0.5 and 0.25 mg/kg of body weight administered for 4 consecutive days, and they were more effective than the standard drugs suramin, diminazene, and quinapyramine. After all selection criteria were applied, three diamidine compounds (DB 75, DB 867, and DB 1192) qualified as lead compounds and were considered to have the potential to act as preclinical candidates against T. evansi infection.

Topics: Animals; Disease Models, Animal; Female; Mice; Parasitic Sensitivity Tests; Pentamidine; Trypanocidal Agents; Trypanosoma; Trypanosomiasis

The key dinitrile intermediates 4a-d were synthesized by reaction of phenacyl bromide 1 and the appropriate 2-amino-5-bromopyridines to yield 3a-d. Suzuki coupling of 3a-d with 4-cyanophenylboronic acid yielded the 2,6-bis(4-cyanophenyl)-imidazo[1,2-a]pyridine derivatives 4a-d. The bis-amidoximes 5a-d, obtained from 4a-d by the action of hydroxylamine, were converted to the bis-O-acetoxyamidoximes which on catalytic hydrogenation in a mixture of ethanol/ethyl acetate gave the acetate salts of 2,6-bis[4-(amidinophenyl)]-imidazo[1,2-a]pyridines 7a-d. In contrast, catalytic hydrogenation of the bis-O-acetoxyamidoxime of 5a in glacial acetic acid gave the saturated analogue 2,6-bis[4-(amidinophenyl)]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine 8. O-Methylation of the amidoximes 5a-d gave the N-methoxyamidines 6a-d. The diamidines showed strong DNA binding affinity, were very active in vitro against T. b. r. exhibiting IC(50) values between 7 and 38nM, but were less effective against P. f. with IC(50) values between 23 and 92nM. Two of the diamidines 7c and 7d were slightly more active than furamidine but less active than azafuramidine in the T. b. r. STIB900 mouse model. Only one prodrug 6b showed moderate activity in the same mouse model.

Topics: Animals; Antimalarials; Antiprotozoal Agents; Combinatorial Chemistry Techniques; Disease Models, Animal; Inhibitory Concentration 50; Mice; Molecular Structure; Plasmodium falciparum; Prodrugs; Pyridines; Trypanosoma brucei rhodesiense