Correlating the Molecular Electrostatic Potentials of Some Organic Peroxides with Their Antimalarial Activities ² Charles W. Jefford,* ,‡ Martin Grigorov, §,| Jacques Weber,* ,§ Hans P. Lu ¨thi, §,⊥ and Jean M. J. Tronchet | Departments of Organic, Physical, and Pharmaceutical Chemistry, University of Geneva, 1211 Geneva 4, Switzerland, and Centro Svizzero di Calcolo Scientifico, CH-6928 Manno, Switzerland Received September 14, 1999 The molecular electrostatic potentials (MEPs) of artemisinin (also known as qinghaosu), yingzhaosu A, and some synthetic analogues have been calculated and studied as a means of distinguishing between high and low antimalarial activity. To facilitate comparison, the dimensionality of the MEP was reduced by Kohonen Neural Network transforms. The reduction revealed that peroxides exhibiting high antimalarial activity are characterized by a continuous strip of negative electric potential surrounding the molecule, whereas peroxides of lesser activity show a broken strip. 1. INTRODUCTION It is now known that antimalarial peroxides, both of natural and synthetic origin, kill the Plasmodium parasite through a mode of action which is entirely different from that of the traditional quinoline-based drugs such as quinine and chlo- roquine. 1 For instance, artemisinin (also known as qinghaosu) (1) and the trioxane BO7 (2) effect their lethal action on the parasite by a process of chemical induction. 2,3 During the trophozoı ¨te stage of the intraerythrocytic cycle within the host, the parasites invade the red blood cells and digest the hemoglobin content as a nutritional source of amino acids. The prosthetic group, heme, released by proteolysis, because of its toxicity to the parasite, is im- mediately oxidized and polymerized to the insoluble malarial pigment, hemozoin. When the host is treated with 1 or 2, the aforementioned detoxification process is interrupted by complexation with heme. For example, 2 by virtue of the flexibility conferred by the cis-fused rings, maneuvers its O-O bond over the iron atom and coordinates with it, forming a complex (3) (Scheme 1). 4 Next, within the complex, a single electron is transferred from the 3d orbital of iron to the σ antibonding orbital of the contiguous peroxide bond, causing it to break. The resulting oxygen radical 4 spontaneously rearranges to the highly reactive primary carbon-centered radical 5 which can then alkylate the protein (PP) of a nearby parasite causing its death. The alkylated protein 6 is then detached, releasing hemozoin. The foregoing mechanism clearly depends on the optimal confluence of several molecular properties in order to produce the ultimate antimalarial pharmacophore. In other words, the parasiticidal action of potent peroxides such as 1 and 2 derives from the efficient operation of the above- mentioned sequence of chemical events, namely, docking with heme, electron transfer, formation of an oxy radical, scission to a primary C-centered radical, and finally, the coup de gra ˆce, alkylation. In a 3D-QSAR study, 5 we showed that hydrophobic features and hydrogen bonding in certain cis- fused bicyclic trioxanes are responsible for binding with heme. Typically, the highest antimalarial activity correlates with those trioxanes which can adopt a conformation that ensures an intimate fit or close docking with heme. As a case in point, the Catalyst program predicted accurately that the activity of the cyclopentenotrioxane 2 exceeds that of the cyclohexeno analogue 7 because conformational acces- sibility to the critical fit is attained in 2, but not in 7. While the foregoing 3D-QSAR study of active anti- malarials confirmed the importance of docking, it provided no information on the electron-transfer process. As such a process is beyond the capability of the Catalyst software, * Corresponding authors. E-mail: jefford@sc2a.unige.ch and jacques.weber@chifi.unige.ch. Telephone: +41-22-702-6530. ² Dedicated to the memory of Dr. Colin Thomson. ‡ Department of Organic Chemistry, University of Geneva. § Department of Physical Chemistry, University of Geneva. | Department of Pharmaceutical Chemistry, University of Geneva. ⊥ Centro Svizzero di Calculo Scientifico. Scheme 1 354 J. Chem. Inf. Comput. Sci. 2000, 40, 354-357 10.1021/ci990276u CCC: $19.00 © 2000 American Chemical Society Published on Web 01/26/2000