The Synthesis of Potential Antimalarials: I. Analogues of Pantothenic Acid. II. N¹-Phenylsulfanilamides. III. Sulfonamidopyrimidines. IV. Quinolinemethanols Related to Quinine

Soon after the start of the war with Japan in 1941 it became apparent that one of the most pressing medical problems facing the United States was the control of malaria. The early conquests by Japan in the Dutch East Indies interfered with the use of quinine for the control of this disease, since the major world production centers of the alkaloid were under enemy control. At the same time it was obvious that much of the fighting would take place in highly malarial regions, especially in the South Pacific Ocean. The synthetic drugs which were available for use against malaria were relatively new and untried. Atebrin was very promising but there were various unpleasant effects attending its use, and it was not certain that it could completely replace quinine. Plasmochin, although extremely active, was of little use as a general drug, due to its great toxicity. Neither of these drugs, nor for that matter quinine itself, acted as a causal prophylactic, a property which would have been extremely desirable in a drug. In this emergency the Committee on Medical Research of the Office of Scientific Research and Development sponsored a large program of research on malaria. One branch of this program was concerned with testing a large number of drugs for possible antimalarial activity, in the hope of finding new classes of active compounds, of discovering more active members of classes of known activity, and possibly of finding a causal prophylactic. To assist this phase of the program the Survey on Antimalarial Drugs was set up to test the available compounds. Most of the drugs tested were examined for activity against avian malaria, although certain compounds which showed exceptional promise were tried out in human malaria. The two tests used most frequently were for activity against P. lophurae in ducks, and against P. gallinaceum in chicks. Many of the drugs which were pasted in this program were compounds immediately available, from the shelves of chemical manufacturers, pharmaceutical houses, etc. In addition a great deal of work in synthetic organic chemistry was sponsored to provide new drugs for testing. This thesis describes a number of syntheses carried out by the author between September 1942 and December 1945, working under a contract between the Office of Scientific Research and Development and the California Institute of Technology. This project waw under the direction of Dr. Joseph B. Koepfli. Being carried out as part of a war research program, this work differs in several respects from the type of work usually described in a thesis. Since the primary object was to prepare the desired compounds as quickly as possible in a given quantity, it was not always necessary to examine reactions critically for conditions of maximum yield and ease of working. If a reaction took place with a low yield, it was often quicker to carry it out several times than to try to find conditions under which the yield might be improved. In several cases interesting side reactions were not iced; these were ignored unless the by-products formed seemed to have a direct bearing on the problem at hand. In addition the work often took on a cooperative aspect, with several members of the project working simultaneously on the same problem and even, on occasion, on the same reaction. In so far as possible I have endeavored to acknowledge assistance with particular problems in the body of this report. The details of the pharmacological action of the compounds whose preparation is described are not discussed. It is the intention of the Survey on Antimalarial Drugs to publish a monograph in which the activities of all the compounds tested will be given. The number designated by SN given following the compounds in this thesis is the number by which these compounds will be designated in the report of the Survey.