Determination of activity of MG-192 against infective African trypanosomes in vitro and in a mouse model

Abstract

Treatment options for trypanosomosis are few and limited, complex to administer and have severe side effects. There is great need for discovery of new drugs that are safe, effective and easy to administer in rural settings. The structure-activity relationship theory (SAR) in drug discovery was explored in this study. This study investigated whether MG-192, a synthetic compound with similar structural features as Pentamidine, a standard trypanocidal drug, has the ability to clear African trypanosome infections. In vitro and in vivo activity of test compound MG-192 on T. b. rhodesiense and T. congolense isolates was investigated. Acute toxicity of MG-192 in mice was determined by injecting the mice with the test compound and observing them for 14 days. The in vitro cultures revealed that MG-192 has anti-trypanosomal properties, with an average MIC of 2.345 × 103 µg/ml ± 1.355 and 3.125 × 103 µg/ml for T. b. rhodesiense isolates KETRI 2537 and KETRI 2538. The T. congolense isolates KETRI 3867 and KETRI 3805 had an average MIC of 3.125 ×103 µg/ml and 3.516 ×103 µg/ml ± 0.552 respectively. Propagation of T. b. gambiense in donor mice did not yield sufficient parasitaemia and the experiment into the parasite could not proceed further. Studies into the acute toxicity effects of MG-192 in mice showed that after both single dose and multiple (5-day) intraperitoneal injections with various doses of MG-192, the no observed adverse effects level (NOAEL) was 1000 mg/kg. Single doses of MG-192 500 mg/kg and 200 mg/kg had an effect on mice body weight and PCV (p < 0.05). Period by drug interaction analysis on multiple administration of MG-192 1000 mg/kg also showed a significant effect on PCV (p= 0.035). The effect of 5-day administration of MG-192 on mice’ organ weight: body weight ratio was significant in the kidneys (in the 200 mg/kg treatment group; p=0.015) and lungs (treatment groups 500 mg/kg; p< 0.001 and 1000 mg/kg; p=0.038). MG-192 did not clear trypanosome infections in vivo but single dose administration of the compound had a significant effect on parasitaemia (p <0.001) of T. b. rhodesiense KETRI 2537. The study revealed that the MG-192 had antitrypanosomal activity against trypanosomes in vitro but did not clear T. b. rhodesiense and T. congolense infections in vivo in concentrations of between 200 mg/kg and 750 mg/kg. The test compound, however, had a significant effect on parasitaemia patterns when mice infected with T. b. rhodesiense KETRI 2537 were treated with a single dose of MG-192. More studies are needed to investigate the pharmacokinetic activity of MG-192 in mice in order to determine how to improve its efficaciousness in clearing trypanosome infections in vivo.