Design, ADME Evaluation, Lewis Acid Catalysed Synthesis and Biological Evaluation of 1,4 Naphthoquinone Derivatives as Antimalarial Agents

In an effort to develop new antimalarials, some 1,4 naphthoquinone derivatives were designed on the basis of results of computational studies reported in previous paper, which showed that 2 nd or 3 rd or both position of 1,4 naphthoquinone is most suitable for better antimalarial activity. When the reaction of 1,4 naphthoquinone was performed without a catalyst several secondary products were formed, but when performed in presence of lewis acid like CeCl3.7H2O,Ce 4+ provides a unique catalytic effect promoted by redox properties with formation of the desired products in very good yields. Therefore compounds have been synthesized using Lewis acid as catalyst, which reduces reaction time and gives better yield. Characterisation of compounds was done using IR, 1H NMR, 13CNMR and mass spectroscopy. All the compounds were screened for intra erythrocytic in vitro antimalarial evaluation against Chloroquine-sensitive (3D7) strain of Plasmodium falciparum using the SYBR Green I fluorescence assay. The results revealed that 2-(2,4-dimethylphenylamino)naphthalene1,4-dione (P2) as most potent compound with IC50 of 1.8 μM. Priyanka Kamaria*, Neha Kawathekar Department of Pharmacy, Shri G.S. Institute of Technology & Science (An Autonomous Institution), 23 Park Road, Indore (M.P.), India. Submission: 26 June 2016 Accepted: 1 July 2016 Published: 25 July 2016 www.ijppr.humanjournals.com Citation: Priyanka Kamaria et al. Ijppr.Human, 2016; Vol. 6 (4): 92-103. 93 INTRODUCTION There is an urgent need for new antimalarial drugs with novel mechanisms of action for implicit control and eradication of malaria. Parasite resistance to almost all existing antimalarial classes, including the artemisinins, have been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to resurgence in the disease which would represent a global health emergency [1,2]. Naphthoquinone pharmacophore impart pronounced biological effects, such as antitumor [3-10], antimycobacterial [11], antiinflammatory, anti-allergic [12], antimalarial [13,14,15] and antileishmanial [16]. The antimalarial mode of action of 1,4 naphthoquinone involves a cascade of redox reactions in the parasite. The postulated bioactivation of the antimalarial 3-benzyl-menadione (a naphthoquinone derivative) is thought to generate redox-active metabolites which, in their oxidized form, are reduced by NADPH in glutathione reductase-catalyzed reactions within the cytosol of infected red blood cells and in their reduced forms, can convert methaemoglobin (Fe III), the major nutrient of the parasite, into the very slowly digestible haemoglobin (Fe II). Consequently, the antimalarial naphthoquinones are suggested to perturb nutrient acquisition and the major redox equilibrium of the targeted infected red blood cells, ultimately results in arrest and death of the malaria parasite at the trophozoite stage [17]. A number of naphthoquinone derivatives (Figure-1) have shown potential antimalarial activity. 1,4-napthoquinones acts by a non-bc1-dependent mechanism and remain potent against atovaquone and chloroquine resistant parasites. The variable capacity of naphthoquinones to accept electrons is due to the electron-attracting or -donating substituents at the quinone moiety which modulate the redox properties responsible for the resulting oxidative stress. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria. www.ijppr.humanjournals.com Citation: Priyanka Kamaria et al. Ijppr.Human, 2016; Vol. 6 (4): 92-103. 94 O O 2-Methyl-1,4 Naphthoquinone (Menadione) O O CF3 2-(4-(trifluoromethyl)benzyl)-3-methylnaphthalene-1,4-dione (Benzyl naphthoquinone) O