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

Abstract

Malaria is a disease caused by protozoans transmitted to humans by infected female Anopheles mosquitoes. According to the WHO report of 2015, there were 214 million cases of malaria with 438,000 deaths worldwide. 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 in developing countries. Currently, there is no effective vaccine for malaria control. In addition, although 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 toward combating 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. This suggests the need to develop new antimalarial drugs that are effective against malaria parasites based on the new mode of action, molecular targets, and chemical structures. In silico studies have shown that sarcosine is able to bind to unique plasmodia proteins (P. falciparum ATCase), whereas aniline can be a ligand to target protein (enoyl acyl carrier protein reductase), hence suppressing the progression of the disease. The main objective of this study was to synthesize and determine the efficacy and safety of antiplasmodial hybrid drug comprising the sarcosine and aniline derivative for management of plasmodial infections. The hybrid drug was synthesized by adding thionyl chloride to sarcosine to form acyl chloride which was then added to aniline to form sarcosine-aniline hybrid molecule. The IC50 of sarcosine-aniline hybrid was 44.80 ± 4.70 ng/ml compared with that of aniline derivative which was 22.86 ± 1.26 ng/ml. The IC50 of control drugs was 2.63 ± 0.38 ng/ml and 5.69 ± 0.39 ng/ml for artesunate and chloroquine, respectively. There was a significant difference between IC50 of sarcosine-aniline hybrid and aniline derivative (p<0.05). There was also a significant difference between sarcosine-aniline hybrid and standard drugs used to treat malaria including artesunate and chloroquine (p<0.05). The ED50 of sarcosine-aniline hybrid drug was 6.49 mg/kg compared with that of aniline derivative which was 3.61 mg/kg. The ED50 of control drugs was 3.56 mg/kg, 2.94 mg/kg, and 1.78 mg/kg for artesunate-aniline hybrid, artesunate, and chloroquine, respectively. There was a significant difference (p<0.05) between ED50 of sarcosine-aniline hybrid and both controls such as aniline derivative, artesunate, artesunate-aniline hybrid, and chloroquine. Cytotoxicity results revealed that sarcosine-aniline hybrid was safe to vero cells with a CC50 of 50.18 ± 3.53 μg/ml. Sarcosine-aniline hybrid was significantly less toxic compared with artesunate, chloroquine, and doxorubicin. Sarcosine-aniline hybrid was efficacious and safe to mice. Therefore, covalent bitherapy should be used in drug development for drug resistance mitigation.

The Synergistic Effect of Combination of Pentagamavunone-1 with Diosmin, Galangin, and Piperine in WiDr Colon Cancer Cells: <i>In vitro</i> and Target Protein Prediction

“…Accordingly, the most potent among the tested natural compounds is galangin, followed by diosmin and piperine (Figure 2c). Based on the classification by WHO (Niyibizi et al 2020), galangin and diosmin are cytotoxic (IC 50 <90 µg/mL), while piperine is not (IC 50 >90 µg/mL). Taken together, galangin is the most promising chemoprevention agent among the three tested natural compounds.…”

“…As predicted, PGV-1 showed a remarkable cytotoxic activity with an IC 50 of 0.08 µM (Figure 2a). Among the tested natural compounds galangin exhibited the strongest cytotoxicity at IC 50 of 26 µM, followed by diosmin and piperine, 133 µM and 603 µM, indicating moderate cytotoxicity and not cytotoxic, respectively (Figure 2b, Table 1), based on cytotoxicity classification by World Health Organization (WHO) (Niyibizi et al 2020).…”

Spectroscopic and biological studies of mixed ligand complexes of transition metal (II) ions with chloroquine and ketoprofen

“…It is found that the magnetic moment of these complexes (1.88 B.M.) is within the permissible range for the d 9 -system with a single unpaired electron [38,39].…”

Progress and challenges in the use of fluorescence‐based flow cytometric assays for anti‐malarial drug susceptibility tests

“…For biochemical assays, the microtechnique was modified to a semiautomatic tritiated hypoxanthine incorporation assay, measuring Plasmodium uptake of radiolabelled hypoxanthine, a nucleic acid precursor, to assess the growth inhibitory effect of anti-malarial drugs [ 19 ] or immune serum [ 20 ]. Given a rapid, more precise and quantitative method, many recent reports have been adopted for the assessment of Plasmodium growth inhibition in experiments [ 21 ] and in a clinical trial setting [ 22 ] and for surveillance of drug resistance in field isolates [ 23 ]. In addition to DNA synthesis-based assays, Plasmodium parasites in intraerythrocytic stages also actively synthesize cell membranes composed of phospholipids; thus, an assay based on incorporation of the radioisotope-labeled phospholipid precursor ethanolamine was developed [ 24 ], allowing an assessment of anti-malarial compounds targeting enzyme functioning in fatty acid biosynthesis [ 25 ].…”