Unambiguous Synthesis and Prophylactic Antimalarial Activities of Imidazolidinedione Derivatives

Abstract

The public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing the burden, to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. WR 182393, a guanidinoimidazolidiondione derivative with potent causal prophylactic antimalarial activity by intramuscular injection, was previously prepared by treatment of chloro-proguanil and diethyl oxalate, yielding a mixture of two closely related isomers. Poor solubility of the mixture made the separation and purification impossible. To overcome the separation problem, new and facile unamgibuous syntheses of the two active components were reported. The new synthetic methods facilitate the synthesis of not only the active components, but also their derivatives. To search for compounds with good oral efficacy, a series of carbamate derivatives of the active components were prepared by the new procedure, many of which showed profound causal prophylactic antimalarial activity against Plasmodium yoelii in mouse by oral administration. PLEASE DO NOT AND ADDRESS(ES).Enter the name and address of the thesis, progress, quarterly, research, special, group organization(s) financially responsible for and study, etc.orazaonsfiacalrepniefrad monitoring the work. DATESCOVERED. Indicate the time during which the work was performed and the report was 10. SPONSOR/MONITOR'S ACRONYM(S). Enter, if written, e.g., Jun 1997 -Jun 1998; 1-10 Jun 1996;;;' available, e.g. BRL, ARDEC, NADC.May -Nov 1998; Nov 1998. with; translation of; report supersedes; old edition number, etc. 5d. PROJECT NUMBER. Enter all project numbers as they appear in the report, e.g. 1F665702D1257; SPONSOR/MONITOR'S REPORT NUMBER(S14. ABSTRACT. A brief (approximately 200 words) ILIR. factual summary of the most significant information.5e. TASK NUMBER. Enter all task numbers as they 15. SUBJECT TERMS. Key words or phrases * appear in the report, e.g. 05; RF0330201; T4112.• identifying major concepts in the report.5f. WORK UNIT NUMBER. Enter all work unit numbers as they appear in the report, e.g. 001; 16. SECURITY CLASSIFICATION. Enter security AFAPL30480105.classification in accordance with security classification regulations, e.g. U, C, S, etc. If this form contains 6. AUTHOR(S). Enter name(s) of person(s) classified information, stamp classification level on the responsible for writing the report, performing...

New imidazolidinedione derivatives as antimalarial agents

“…Search of non-8-AQ new antimalarial drugs with prophylactic and/or radical curative activity to replace 8-AQ antimalarial drugs, such as primaquine (PQ) and tafenoquine (TQ), is the paramount interest of this laboratory in recent years. [1][2][3][4] Imidazolidinedione derivatives, such as compound WR182393 (IZ), is one of the very few classes of compounds with liver stage antimalarial activity. It was first prepared and tested in exoerythrocytic (EE) mouse model in early 1970s and was later found to have radical curative and causal prophylactic activity in Rhesus infected with sporozoites of Plasmodium cynomolgi.…”

Facile synthesis of 2,4‐diamino‐6‐alkyl‐ or 6‐aryl‐pyrimidine derivatives

“…Ethyl benzoylacetate (15 mL) was added dropwise to a suspension of 3,4-dichlorophenylguanidine (1a, 7.23g. 35.4 mmol) [2] in 100 mL of anhydrous DMF. The mixture was heated at 100 C for 48 h. After cooling, the reaction mixture was poured into 500 mL of ice water.…”

“…Ethyl benzoylacetate (11.7 mL) was added dropwise to a suspension of isopropylguanidine (1b) [2] (2.3 g, 22.7 mmol) in 50 mL of anhydrous DMF. The reaction mixture was heated at 100 C for 3 days.…”

“…As part of our efforts in search of malaria prophylactic and/or therapeutic agents, a series of imidazolidinedione (IZ) derivatives was found to possess profound activity against liver stage malarias in rodent and nonhuman primate models [1][2][3][4]. Subsequently, the IZ compounds were found to metabolize to s-triazine derivatives in microsomal preparations and in rodents [4].…”

A facile one pot synthesis of 2, 4‐diamino‐6‐substituted s‐triazine derivatives

“…As part of our efforts in search of malaria prophylactic and/or therapeutic agents, a series of imidazolidinedione (IZ) derivatives were found to possess profound activity against liver stage malaria in rodent and non-human primate models [1][2][3][4]. Subsequently, the IZ compounds were found to metabolize to s-triazine derivatives in microsomal preparations and in animals [4].…”