Synthesis, alkylating activity and physicochemical study of nitrogen mustard agent for brain delivery

On the structural pattern of nikethamide which is a potent central nervous system (CNS) stimulant, it was designed to link N,N-bis(2-chloroethyl)amino moiety as alkylating agent to nicotinic acid by an amide bond in the hope to obtain a CNS antitumor agent (Nicotinic-mustard). The Nicotinic-mustard agent was solid at room temperature and stable for more than one week when stored at less than 0 o C. The in vitro chemical alkylation activity (NBP) of Nicotinic-mustard was comparable to that of N,N-bis(2-chloroethyl)amine as standard alkylating agent. The log P value of Nicotinic-mustard was analyzed (miLogP and MlogP) and found to be increased lipophilicity for the Nicotinic-mustard construct compared with the parent compound nicotinic acid. Value of polar surface area for the Nicotinic-mustard agent (33 A 2 ) predicts that >90% of any amount present in the intestinal tract will be absorbed. The physicochemical potential of this compound to penetrate the BBB such as Log BB, Polar surface area, rule of five, number of NH or OH hydrogen bond donors and no value was computed through online software program and the values obtained for the Nicotinic-mustard suggest a good brain penetration.