Chemical Synthesis, Efficacy and Safety of Antimalarial Hybrid Drug Comprising of Sarcosine and Aniline Pharmacophores as Scaffolds

Abstract

Malaria is a disease caused by protozoan plasmodium transmitted to humans by infected female Anopheles mosquitoes. According to WHO report of 2015, there were 214 million worldwide cases of malaria with 438,000 deaths. Ninety percent of world’s malaria cases occur in Africa, where the disease is recognized as a serious impediment to economic and social development. Despite advancement in malaria research, the disease continues to be a global problem especially for developing countries. Currently, there is no effective vaccine for malaria control. In addition, though there are effective drugs for treatment of malaria, this could be lost to the drug resistance in different Plasmodium species. The most lethal form is caused by P. falciparum which has developed resistance to many chemotherapeutic agents and possibly to the current drugs of choice. Reducing the impact of malaria is a key to achieving the sustainable development goals which are geared towards eradicating the disease. Covalent bitherapy is a rational and logical way of drug design which entails joining a couple of molecules with individual intrinsic action into a unique agent, hence packaging dual-activity into one hybrid molecule. The main objective of this study was to synthesize, determine the efficacy and safety of antiplasmodial hybrid drug comprising of sarcosine and 3-Chloro-4-(4-chlorophenoxy) aniline for management of plasmpodial infections. The hybrid drug was synthesized by adding thionyl chloride to sarcosine in order to form acyl chloride which was added to aniline to form sarcosine-aniline hybrid drug. In vivo efficacy was done using mice and in vitro cytotoxicity assay was done using vero cells. Data for in vivo drug assays and cytotoxic assays were analyzed using Microsoft excel software from which ED50 and CC50 of each drug concentration was determined. Using SPSS software version 20, one way ANOVA was applied for comparing in vivo efficacy and cytotoxicity of hybrid drug against control drugs. In vivo evaluation was carried out using P. berghei ANKA strain sensitive to quinolone. The ED50 of sarcosine-aniline hybrid drug was 6.49mg/kg compared to that of aniline derivative which was 3.61mg/kg. The ED50 of control drugs were 3.56mg/kg, 2.94mg/kg and 1.78 mg/kg for artesunate-aniline hybrid drug, artesunate and CQ respectively. There was a significant difference (P<0.05) between ED50 of sarcosine-aniline hybrid and both controls including 3-Chloro-4-(4-chlorophenoxy) aniline, artesunate, artesunate-aniline hybrid and chloroquine. Cytotoxicity results revealed that hybrid drug was safe to vero cells with a CC50 of 50.18±3.53μg/ml, whereas the CC50 of artesunate, chloroquine and doxorubicin were 19.69±3.26, 57.96±3.85 and 1.96 ± 0.59 μg/ml respectively. Sarcosine-aniline hybrid was significantly less toxic compared to artesunate and doxorubicin (P < 0.05). Sarcosine- aniline hybrid drug was also safe to mice, as no mice died and no significant loss of weight after administering them with 2000mg/kg of the hybrid for 14 days. Therefore, covalent bitherapy should be used in drug development for drug resistance mitigation. KEY WORDS: Chemical synthesis, ED50, CC50, Antimalarial resistance, Sarcosine-aniline hybrid.