QSAR of Antimalarial Cyclic Peroxy Ketals II: Exploration of Pharmacophoric Site Using AM1 Calculations

A series of antimalarial cyclic peroxy ketals (n=20) have been subjected to energy minimization using AM1 method, and Wang–Ford charges of the non-hydrogen common atoms (Figure 1), obtained from molecular electrostatic potential surface of the energy minimized geometries, have been used to model the antimalarial activity against P. falciparum. It is found that the difference in charges between the peroxy oxygens contribute positively to the activity, and this is in good agreement with the mode of antimalarial action of the peroxy compounds involving breakage of the peroxy bridge by the haem-iron within the parasite. It is hypothesized that difference in charges between two peroxy oxygens may facilitate the bond breakage. It is further found that the activity increases with increase in negative charge of the methoxy carbon of the common fragment of the molecule. This is related with possible secondary electronic interaction with the positively charged side chains of the histidine rich protein of P. falciparum. Attempt was made to incorporate steric and indicator parameters which emerged as important contributors from previous Hansch analysis. The present results support the previous observations that bulky phenyl ring substituents and a seven-member carbocylic ring attached to the peroxy bridge-containing ring are conducive to the activity.