Structure identification and prophylactic antimalarial efficacy of 2-guanidinoimidazolidinedione derivatives

Guan, Jian; Zhang, Quan; Gettayacamin, Montip; Karle, Jean M.; DiTusa, Charles A.; Milhous, Wilbur K.; Skillman, Donald R.; Lin, Ai Jeng

doi:10.1016/j.bmc.2004.10.052

Cited by 17 publications

(53 citation statements)

References 8 publications

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“…The residue was applied to a silica gel flash column and eluted with 2.5% MeOH in CHCl 3 to give 35% yield of compound 2b as a white solid. 1 …”

Section: Methodsmentioning

confidence: 97%

“…Preparative TLC was performed using silica gel GF Tapered Uniplates (Analtech, Newark, DE). 1 H NMR and 13 C NMR spectra were recorded in deuteriochloroform, unless otherwise noted, on a Bruker Avance 300 spectrometer (Bruker Instruments, Wilmington, DE). Chemical shifts are reported in parts per million on the d scale from an internal standard of tetramethylsilane.…”

Section: Methodsmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Sathunuru

Meléndez

et al. 2010

Journal of Heterocyclic Chem

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in Wiley Online Library (wileyonlinelibrary.com).Facile methods were developed to prepare a series of 6-phenyl and 6-alkyl-2,4-diaminopyrimidine derivatives. The pyrimidine ring of the final products was constructed by treatment of a 1,3-dicarbonyl derivative with an amidine or guanidine. The 6-phenyl-pyrimidine derivatives were also prepared by Suzuki coupling reaction, using 2-methylthio-4,6-dichloropyrimidine as the starting material.

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“…The residue was applied to a silica gel flash column and eluted with 2.5% MeOH in CHCl 3 to give 35% yield of compound 2b as a white solid. 1 …”

Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Wang

Sathunuru

Meléndez

et al. 2010

Journal of Heterocyclic Chem

Self Cite

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show abstract

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Sathunuru

Meléndez

Kozar

et al. 2008

Journal of Heterocyclic Chem

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2). RefluxA novel and facile one-pot procedure for the preparation of 2,4-diamino-6-substituted-s-triazine derivatives (IIa-n) was reported. The scope of its application was demonstrated with a number of examples. The new procedure involved treatment of proguanil or chloroproguanil with acyl chloride or alky chlorooxoacetate in pyridine at ice cold temperature followed by reflux overnight to give good yields of the desired products.

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“…Since oral administration is the preferred route of administration, especially for those diseases requiring a prolonged course of treatment, then a prodrug approach is a plausible solution to circumvent the drawback of limited oral absorption. Carbamates were introduced earlier as potential prodrugs for guanidine derivatives [25,[33][34][35]. In this work a number of carbamate derivatives were prepared and evaluated as potential prodrugs for the bis-guanidine series.…”

Section: Introductionmentioning

confidence: 99%

Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

Arafa

Ismail

Munde

et al. 2008

European Journal of Medicinal Chemistry

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A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate BOC protected bisguanidines 5a,b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c-f were obtained in three steps starting by reacting the diamines 4a,b with ethyl isothiocyanatoformate to give the carbamoyl thioureas 7a,b. Subsequent condensation of 7a,b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a-f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c-f were obtained via the base catalyzed decarbamoylation of 8a-f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by T m values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.

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Structure identification and prophylactic antimalarial efficacy of 2-guanidinoimidazolidinedione derivatives

Cited by 17 publications

References 8 publications

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

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

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

Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

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