Antimalarials. 12. Preparation of carbon isosteres of selected 4-pyridinemethanols as suppressive antimalarials.

Four carbon isosteres related to the highly active 4-pyridylcarbinolamines were prepared and evaluated for suppressive antimalarial activity against Plasmodium berghei in mice. Three of the four examples possessed significant activity but were approximately one dose level less active than the corresponding pyridines.

Antimalarials. 9. Methylthio- and methylsulfonyl-substituted 9-phenanthrenemethanols.

Nine di- and trisubstituted 9-phenanthrenemethanols bearing methylthio and methylfulfonyl substituents in the 2 and/or 6 positions of the phenanthrene nucleus were prepared and screened for antimalarial activity against Plasmodium berghei in mice. Six of the nine compounds were curative at or below 160 mg/kg. The most active structures contained a methylthio substituent in combination with two chlorine atoms.

Antimalarials. 13. 5-Alkoxy analogues of 4-methylprimaquine.

A series of nuclear and side-chain analogues of 4-methylprimaquine incorporating an alkoxy group in the 5-position of the quinoline nucleus has been prepared. The compounds were tested for suppressive antimalarial activity against Plasmodium berghei in mice and for radical curative antimalarial activity against Plasmodium cynomolgi in the rhesus monkey. Although the toxicity problems characteristic of the 8-aminoquinolines were not overcome, several of the compounds, surprisingly, were highly effective as both blood and tissue schizonticidal agents.

Antimalarials. 10. Synthesis of 4-substituted primaquine analogues as candidate antimalarials.

Primaquine (I) has been extensively used in combination with other drugs in the radical cure of relapsing malaria as well as for prophylaxis or the interruption of transmission. This, coupled with the activity data reported for 4-methylprimaquine (II), has led to the synthesis of a series of 14 4-substituted analogues of I. In addition, three side-chain analogues of II were prepared. The compounds were tested for suppressive antimalarial activity against Plasmodium berghei in the Rane mouse screen and for radical curative activity against Plasmodium cynomolgi in the rhesus monkey. Four of the 17 compounds prepared (1a, 9c, 15, and 17) exhibited activity in at least one of the test systems.

Hydantoins as antitumor agents.

A series of 27 hydantoins was prepared and tested as antitumor agents. These were variously substituted in the 5 position but with special emphasis on the substituents (chloro, acetyl, chloroacetyl, and methyl) in the 1 and/or 3 positions. The most active compound was 5,5-bis(4-chlorophenyl)-1,3-dichlorohydantoin with a T/C value of 190% against P-388 lymphocytic leukemia in mice.

Antimalarials. 7.2,8-Bis(trifluoromethyl)-4-quinolinemethanols.

Based on the high antilalarial activity of alpha-(2-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol, ten additional 2,8-bis(trifluoromethyl)-4-quinolinemethanols were prepared in which the amino alcohol side chain was structurally varied. Synthesis of the compounds is described and antimalarial activity data against Plasmodium berghei are presented and discussed in terms of the structure variations.

Antimalarials. 8. Synthesis of amino ethers as candidate antimalarials.

Based upon the antimalarial activities demonstrated by compounds I and II a series of amino ethers represented by structures III-VI was synthesized. These structures incorporated several modifications of compound II. The compounds prepared displayed no activity in either the Rane P. berghei mouse screen or the Rane P. gallinaceum sporozoite-induced chick test.

Cyclopentenylcytosine. A carbocyclic nucleoside with antitumor and antiviral properties.

Cyclopentenylcytosine (CPE-C, 2), a pyrimidine analogue of the fermentation derived carbocyclic nucleoside neplanocin A, has been synthesized from the optically active cyclopentenylamine 3b by two synthetic routes. CPE-C demonstrates significant antitumor activity against both the sensitive and ara-C resistant lines of L1210 leukemia in vivo. Multiple long term survivors are produced in both tumor models. The compound also gives 100% growth inhibition of the solid human A549 lung and MX-1 mammary tumor xenografts grown in athymic mice. Good activity is also observed against a third human tumor xenograft model, metastatic LOX melanoma. CPE-C has significant activity against both DNA and RNA viruses in vitro. Potent activity is observed against HSV-1 (TK+ and TK-), HSV-2, vaccinia, cytomegalovirus, and varicella-zoster virus. Good activity is also found against a strain of influenza virus (Hong Kong flu), vesicular stomatitis virus, Japanese encephalitis virus, and Punta Toro virus.