Abstract

TO DESIGN STRUCTURALLY NOVEL COMPOUNDS TARGETING FALCIPAIN AS ANTI MALARIA DRUG DELIVERY SYSTEM

Dilend Patle*, Dr. Arun Patel, Shailendra Patel, Bhavesh Patel and Neelesh Kumar Dwivedi

Abstract

The current research work investigates the design, synthesis and biological evaluation of Plasmodium falciparum proteases. This is achieved by examining the effect of inhibitor design, especially warheads, on percentage inhibition (IC50 values) and generation of structure activity relationships (SAR) between cysteine protease falcipain-2 (Series I to IV), and serine protease ClpP (caseinolytic proteases) inhibitors (Series V and VI).Falcipain-2 protease has been a subject of intense research over the past two decades. Inhibition of Plasmodium falcipain-2 proteases is a strategy to develop novel drugs against malaria. As per the pharmacophoric requirements of falcipain-2 inhibitors, three different non-peptidic small molecule series namely, 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N- phenylacetamide derivatives (Series I), 1-(4- (substituted)piperazin-1-yl)-2- (phenylamino) ethanone derivatives (Series II), and 2-(4- (substituted benzoyl)piperazin-1-yl)- N-phenylacetamide derivatives (Series III), were designed using ligand-based approach. The ‘Lipinski’s Rule of Five’ was adopted while designing the molecules to attain better pharmacokinetic profile. These carboxamides were synthesized from the starting material, aniline (Series I and III), or piperazine (Series II), in a sequence of reactions, respectively.

Keywords: Plasmodium falciparum proteases, Maleria, Drug Design, Carboxamides, Piperazine.