Previous studies on the filaricidal properties of various drugs in naturally acquired infections with Litomosoides carinii in cotton rats,1-5 Dirofilaria immitis in and Wuchereria bancrofti in human patients8? have been confined largely to organometallic compounds. With the exception of certain cyanine dyes: no chemical compound not containing antimony or arsenic has been shown to produce marked filaricidal activity in any of the above hosts. Moreover, the above classes of compounds produce their maximum effects when administered parenterally.During the course of a screening program for filaricides in these laboratories, using cotton rats naturally infected with Litornosoides carinii as test animals, marked activity was found with a number of piperazine compounds. The most active members of the series studied produce filaricidal effects in cotton rats quite different from any other known group of compounds, in that (1) an immediate reduction in microfilariae occurs following the first dose, (2) the adult worms are killed slowly, after prolonged treatment, and ( 3 ) oral administration is equally as effective as parenteral administration. Subsequent investigations showed that these effects could be carried over to Dirofilaria-infected dogs, and to human patients infected with Wuchereria bancrofti.The results obtained in cotton rats and dogs with various piperazines, and in particular with 1-diethylcarbamyl-4-methylpiperazine hydrochloride (Hetrazan), form the subject of this paper. The general procedures used for studying the action of chemical compounds in cotton rats and dogs have been discussed previously.1°The first piperazine compound found to produce a measurable effect against Litomosoides carinii was 1-carbethoxy-4-methylpiperazine hydrochloride. I n intraperitoneal doses ranging from 6.25 to 200 mg. per kg. twice daily, this compound produced marked reductions in circulating microfilariae (TABLE 1 ) . Oral doses within the same range were found to be equally effective against microfilariae. Reductions as high as 95 per cent occurred in some animals on the first day after treatment was initiated, and were sustained as long as treatment was continued. Very little effect with this compound could be demonstrated against adult worms, however, particularly in early stages of the investigation, and a number of related compounds were therefore prepared by our organic chemistry division in order to determine whether the activity could be enhanced.The piperazine nucleus itself showed no activity, nor did any of its components. A carbethoxy radical in position "l", with various substitu- Types of Piperazines Studied.(128)

The antimalarial properties of crude extracts of plants belonging to the genera Dichroa and Hydrangea have been described in previous papers in this series (Duggar, in press;Ablondi et at. 1952; Hutchings et at. 1952). After the activeprinciple was isolated in crystalline form from the leavesof a varietyof Hydrangea sp. (Ablondi et at. 1952), degradation (Hutchings et at. 1952) and synthesis (Baker et at. 1952) proved it to be an alkaloid, 3-[@-keto-7-(3-hydroxy-2-' piperidyl)propyl]-4-quinazolone. The naturallyoccurringalkaloidwas found to have a quinine equivalent of approximately 100 when tested in ducks infected with Plasmodium lophurae, and the dl form of the alkaloid prepared synthetically was about 3@as effective. Previous studies of alkaloids isolated from DichroG febrifuga, and tested against P. gallinaceum in chickens (Coatney et at. 1950), P. lophurae in ducks (Henderson et at. 1949), P. relictum in canaries (idem), and P. cynomolgi in monkeys (idem), have given quinine equivalents of from 64 to 148. Among the names given to the naturally occurring alkaloids of Dichroa febrifuga have been Dichroine (Chou et at. 1947), y-Dichroine (Henderson et at. 1949; Chou et at. 1948), and Febrifugine (Henderson et at. 1949). Febrifugine has been reported to be active against the Chesson strain of P. vivax in humans (Coatney etat.1950).It has been demonstratedthat Febrifugine and thenat urally occurring antimalarial alkaloid isolated from Hydrangea sp. in these laboratories areidentical (Ablondietat.1952).Since the alkaloid from Hydrangea possessed a high quinine equivalent, and a method of synthesis was accomplished, it was considered desirable to investi gate related quinazolones for antimalarial activity. The results of assays of 54 synthetic quinazolones against P. lophurae in ducks are described herein, and further data will be presented as the series is expanded. METHODSWhite Pekin ducklings, 2 weeks old and about 200 grams in weight were used as experimental hosts. Infections with P. lophurae were produced by injecting intravenously 0.5 cc. of citrated blood from a heavily parasitized donor bird. The peak ofparasitemia was reachedon the 5th day in control birds, and blood smears were taken at that time to determine the effects of treatment. All of the compounds listed in the tables were soluble in water, and were usually supplied in the form of the hydrochloride salt. They were administered orally by tube twice daily for 3@ days. One dose was given on the day of inoculation, with two doses daily thereafter for 3 days. The dosage in milligrams per kilogram 768

The general term "filariasis" includes several diseases in man and other vertebrates caused by slender, parasitic, nematode worms located in the circulatory and lymphatic systems, muscles, serous cavities or connective tissues. The microfilariae or prelarval forms are discharged by the adult worms into the blood, lymphatics, or tissues of the hosts. Intermediate hosts (mosquitoes or biting flies) are required for the completion of the life cycle.In man, several species of filaría are known, the most important being Wucher-143 SUMMARY Several new derivatives of piperazine have been prepared. The activity of these and other derivatives of piperazine as antifilarial agents has been reported.

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