Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities.

BACKGROUND & OBJECTIVES: Due to the rapid increase of drug resistance in Plasmodium parasites, there is a pressing need of developing new antiplasmodial drugs. In this study, new amodiaquine (AQ) analogs were synthesized, followed by an evaluation of their antiplasmodial activity. METHODS: A new series of quinoline derivatives containing N-alkyl (piperazin-1-yl)methyl benzamidine moiety was synthesized by reacting 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzonitrile with appropriate primary amines. The synthesized compounds were investigated for inhibitory activity by inhibition test of heme detoxification (ITHD). Their antiplasmodial activity was then evaluated using the classical 4-day suppressive test (Peter's test) against Plasmodium berghei-infected mice (ANKA strain). RESULTS: The results showed that the percentage of heme detoxification inhibition in the active compounds was 90%. The most promising analogs, N-butyl-4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzamidine (compound 1e), and 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl)]-N-(4-methylpentan-2-yl)benzamidine (compound 1f) displayed 97.65 and 99.18% suppressions at the doses of 75 and 50 mg/kg/day, respectively. Further, the mean survival time of the mice treated with these compounds was higher than that of the negative control group. INTERPRETATION & CONCLUSION: The newly synthesized amodiaquine analogs presented sufficient antiplasmodial activity with excellent suppressions and high in vitro heme detoxification inhibition. Higher mean survival time of the mice treated with synthetic compounds further confirmed the in vivo antimalarial activity of these new AQ analogs. Therefore, these compounds have the potential to replace common drugs from 4-aminoquinoline class. However, further investigations such as pharmacokinetic evaluations, cytotoxicity, toxicity, and formulation seem to be necessary.

Synthesis and antiplasmodial activity of novel phenanthroline derivatives: An in vivo study.

OBJECTIVES: Due to the rapid increased drug resistance to Plasmodium parasites, an urgent need to achieve new antiplasmodial drugs is felt. Therefore, in this study, the new synthetic phenanthroline derivatives were synthesized with antiplasmodial activity. MATERIALS AND METHODS: A series of 1,10-phenanthroline derivatives containing amino-alcohol and amino-ether substituents were synthesized via facile procedures, starting with 5,6-epoxy-1,10-phenanthroline. Their antiplasmodial activity was then evaluated using Peter's 4-day suppressive test against Plasmodium berghei-infected mice (ANKA strain). Furthermore, the mean survival time of the mice treated with synthetic compounds was compared with the negative control group. RESULTS: The results demonstrated that the compounds 6-(3-(dibutylamino)propylamino)-5,6-dihydro-1,10-phenanthroline-5-ol(7b) at the dose of 150 mg/kg/day and 4-(1,10-phenanthroline-5-yloxy)-N, N-dipropylbutan-1-amine (8b) at the dose of 15 mg/kg/day have 90.58% and 88.32% suppression, respectively. All synthetic compounds prolonged the mean survival time of treated mice in comparison with negative control groups, indicating the in vivo antiplasmodial activity of these new compounds. CONCLUSION: The present study is the first attempt to achieve new, effective synthetic compounds based on phenanthroline scaffold with the antiplasmodial activity. However, more research is needed to optimize their antimalarial activity.