Synthesis of dicationic diaryltriazines nucleic acid binding agents

Spychala, Jaroslaw; Dw, Boykin; Wilson, W. David; Zhao, Min; Tidwell, R. R.; Dykstra, Christine C.; Hall, J. E.; Jones, S. K.; Schinazi, R. F.

doi:10.1016/0223-5234(94)90061-2

Cited by 27 publications

(15 citation statements)

References 24 publications

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“…Analogs of furamidine in which the furan ring has been replaced by pyrrole [136], thiophene [136], and other five-membered ring units have been studied [137]. We have also replaced the central ring with six-membered rings including pyridine [138], pyrimidine [139][140][141], pyridazine [137], and triazine [142]. While these modifications have led to a number of compounds with both significant DNA affinity and antimicrobial activity, especially in the pyrimidine series, none appeared to have significant advantages over the furan analogs.…”

Section: Antimicrobial Activity Of Furamidine and Analogsmentioning

confidence: 99%

Dicationic DNA Minor Groove Binders as Antimicrobial Agents

Tidwell¹,

Boykin

2002

Small Molecule DNA and RNA Binders

159

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Section: Antimicrobial Activity Of Furamidine and Analogsmentioning

confidence: 99%

Dicationic DNA Minor Groove Binders as Antimicrobial Agents

Tidwell¹,

Boykin

2002

Small Molecule DNA and RNA Binders

159

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“…53 The central five membered furan ring has also been replaced by the six member ones pyridine, 54 pyrimidine, [55][56][57] pyridazine, 53 and triazine. 58 These modifications have led to compounds with both potent DNA affinity and antimicrobial activity, however none appeared to be more advantageous than the furan analogs and a number showed much reduced activity. In summary we have shown that 2,5-diphenylfuran and 2,4-diphenylfuran diamidines are highly effective antimicrobial agents in several animal models when administered intravenously.…”

Section: Antimicrobial Activity Of Furamidine and Its Analogsmentioning

confidence: 99%

Antimicrobial activity of the DNA minor groove binders furamidine and analogs

Boykin¹

2002

J. Braz. Chem. Soc.

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Análogos arílicos de diamidinas da pentamidina e do berenil que interagem com a fenda menor de DNA estão sendo sintetizados com amplo espectro de atividade antimicrobiana. Várias séries de análogos da furamidina, 1,5-bis[4-amidinofenil]furano foram descritas e apresentaram boa potência quando administradas de forma intravenosa. Entretanto, elas foram inativas quando administradas oralmente. As pró-drogas do tipo amidoxima e carbamato dessas furamidinas são potentes quando administradas oralmente. Atualmente uma dessas pró-drogas, a bis-O-metiloxima está em estudos clínicos de Fase II.Aryl diamidine analogs of pentamidine and berenil that bind to the minor groove of DNA have been developed which show broad spectrum antimicrobial activity. Several series of analogs of 2,5-bis[4-amidinophenyl]furan (furamidine) have been described which are quite effective when given intravenously, however they are ineffective on oral administration. Amidoxime and carbamate prodrugs of furamidine are quite effective when given orally. One of these prodrugs, a bis-O-methylamidoxime is currently in Phase II clinical trials.

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“…Aromatic dicationic compounds, including bisbenzamidines and dicationically substituted bisbenzimidazoles and carbazoles, have excellent experimental anti-Pneumocystis activities (14,40,46,48,50,51) and are also active against other microbial pathogens, including protozoan parasites (2-5, 10, 38, 41, 43, 44), fungi (45), and some viruses (25-27, 49, 53). Aromatic dications also possess other pharmacological properties, including antiinflammatory and anticoagulant activities (29)(30)(31)(32)(33)(34)(35)(36)(37).…”

mentioning

confidence: 99%

Anti- Pneumocystis Activities of Aromatic Diamidoxime Prodrugs

Hall¹,

Kerrigan²,

Ramachandran³

et al. 1998

Antimicrob Agents Chemother

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Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

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Synthesis of dicationic diaryltriazines nucleic acid binding agents

Cited by 27 publications

References 24 publications

Dicationic DNA Minor Groove Binders as Antimicrobial Agents

Dicationic DNA Minor Groove Binders as Antimicrobial Agents

Antimicrobial activity of the DNA minor groove binders furamidine and analogs

Anti- Pneumocystis Activities of Aromatic Diamidoxime Prodrugs

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