Two lead drug designs based on chloramphenicol as the parent structure, which express alkylation activity with potential for clinical applications.

Abstract

Chloramphenicol is a bacteriostatic antibiotic which acts primarily as an inhibitor of bacterial protein synthesis. Modification of chloramphenicol structure was accomplished by replacing the two hydroxyl groups (-OH) with a chlorine atom for LEAD-1 or a chloroethyl ether group (-OCH(2)CH(2)Cl) for LEAD-2. The resulting daughter compounds expressed significant alkylating activity at physiological temperature of 37 degrees C and at pH 7.4. Alkylation activity was evaluated after reaction with guanosine 5'-diphosphate (GDP), L-serine, L-glutamic acid, and p-chloroaniline. The partition coefficient (log P) was determined for chloramphenicol, LEAD-1 and LEAD-2 to be 0.854, 3.409 and 3.10, respectively. The molecular dipole of chloramphenicol, LEAD-1 and LEAD-2 was calculated to be 5.804, 3.961 and 4.097 Debye, respectively. All three structures showed zero violations of the Rule of 5, which indicates good bioavailability. Values for polar surface area (TPSA) indicate an intestinal absorption of 51% and 35% for LEAD-1 and LEAD-2, respectively. The reduction to only one proton donor in LEAD-1 and LEAD-2 structures (chloramphenicol having three proton donors) indicates an improvement of membrane penetration compared to chloramphenicol. (13)C NMR analysis of molecular structures was accomplished and fast atom bombardment mass spectrometry analysis of a reaction mixture showed LEAD-1 alkylation of guanosine 5'-diphosphate.