Abstract

Quantum Medicinal Chemistry in the design of Anti-malarial agents

Prasad Bharatam, Professor, NIPER Mohali

Divalent N(I) compounds ( ::N(?L)2? ) are systems with bicoordinated nitrogen in N(I) formal oxidation state. It was found that several therapeutically important compounds including like biguanide derivatives (metformin.HCl and proguanil.HCl), (thiazol-2-yl)guanidine derivatives (famotidine, ebrotidine, zaltidine, tuvatidine, tiotidine), guanylthiourea derivatives and pyridyl-2-thiazolamine derivatives, etc. belong to this class with low-valent state of nitrogen. This class of compounds has been found to be characterized by two lone pairs on the central nitrogen, very similar to the central carbon in carbones (::C(?L)2). The new bonding environment for nitrogen (named Nitreones) is clearly different from the nitrenium ions NR2?. Our previous in silico studies on guanylthiourea class of compounds have shown similarity in the molecular electrostatic potential surfaces of the guanylthiourea derivatives in protonated form and pyrimidine nucleus of pyrimethamine. Further this class of compounds contained all the pharmacophoric features developed through molecular modeling analysis. In protonated form guanylthiourea derivatives show divalent N(I) character which is essential to predict the activity of the active moiety. This class is further being developed as a potential nucleus for antimalarial drug therapy. In vitro studies were carried out and two compounds from this class have shown activity in micro-molar range (100µM and 400nM).