The Pharmacology, Mode of Action and Therapeutic Potentialities of Stilbamidine, Pentamidine, Propamidine and Other Aromatic Diamidines—a Review

Schoenbach, Emanuel B.; Greenspan, Ezra M.

doi:10.1097/00005792-194809000-00003

Cited by 117 publications

(31 citation statements)

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“…On substituting imidazolino groups for amidino groups, the antifungal activities of type A compounds generally diminished. This detrimental effect was less pronounced with the more active indoles (6, 4) than with the benzofurans (8,7) or benzothiophenes (17,13). Less disadvantageous was the replacement of the amidino groups by guanidino groups, as shown by 10 and 7 and by 19 and 13.…”

Section: Resultsmentioning

confidence: 98%

“…However, the isosteric replacement of -NH-by -S- (15) ( 13,15,14,12). Substitution of an extra amino group in position 3 decreased the activity (compare 5 with 4 and 16 with 13).…”

Section: Resultsmentioning

confidence: 99%

“…Investigations on therapeutic use of synthetic diarylamidines led to the discovery of the trypanocidal drugs stilbamidine, pentamidine, and Berenil (2,13,16). Some early results (9,11,(14)(15)(16) pointed out that such trypanocidal diarylamidines might also be endowed with antibacterial and antifungal activities.…”

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confidence: 99%

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Antifungal and antibacterial activities of diarylamidine derivatives

Anné¹,

Clercq²,

Eyssen³

et al. 1980

Antimicrob Agents Chemother

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The antifungal and antibacterial properties of a series of 70 diarylamidine derivatives were evaluated. Several of these compounds exhibited considerable antimicrobial potency. A survey of the structure-activity relationship demonstrated that minor structural variations resulted in significant changes of antimicrobial activity. In general, the structural features required for antifungal activity coincided with those required for antibacterial activity. Both the antifungal and the antibacterial properties of the diarylamidines depended on the presence and the positions, of both amidino groups, on the nature of the central bridge connecting the two aryl moieties, and on the nature of these aryl residues (preferably indole). The most active compound was evaluated for its activity against Candida albicans infection in mice.

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Section: Resultsmentioning

confidence: 98%

“…However, the isosteric replacement of -NH-by -S- (15) ( 13,15,14,12). Substitution of an extra amino group in position 3 decreased the activity (compare 5 with 4 and 16 with 13).…”

Section: Resultsmentioning

confidence: 99%

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Antifungal and antibacterial activities of diarylamidine derivatives

Anné¹,

Clercq²,

Eyssen³

et al. 1980

Antimicrob Agents Chemother

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“…Significantly, none of the melaminophenyl arsenicals have any prophylactic activity in rodents when subsequently challenged with trypanosomes (7), correlating with cRU15 showing moderate to high resistance against these compounds (26-, 69-, and 121-fold for melarsen oxide, melarsoprol, and trimelarsen, respectively) (14). In contrast, with the notable exception of berenil (27), all of the diamidines possess considerable prophylactic activity (7,28) with cRU15 showing low resistance to pentamidine, stilbamidine, and propamidine (1.6-, 5.7-, and 7.7-fold, respectively) versus moderate resistance to berenil (24-fold) (14). Although comparative studies failed to distinguish between the prophylactic activity of pentamidine and stilbamidine (29), radiotracer studies in mice suggest that stilbamidine is excreted more rapidly than pentamidine (50% elimination in 2 and 5-6 days, respectively) (30 -32).…”

Section: Discussionmentioning

confidence: 99%

Uptake of Diamidine Drugs by the P2 Nucleoside Transporter in Melarsen-sensitive and -resistant Trypanosoma brucei brucei

Carter¹,

Berger²,

Fairlamb³

1995

Journal of Biological Chemistry

186

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The African trypanosome, Trypanosoma brucei brucei, possesses at least two nucleoside transporter systems designated P1 and P2, the latter being implicated in the selective uptake of melaminophenyl arsenical drugs. Since arsenical-resistant trypanosomes show cross-resistance in vivo to aromatic diamidines, we have investigated whether these drugs are also substrates for the P2 nucleoside transporter. In melarsen-sensitive T. b. brucei, the diamidines, including the commonly used trypanocides, pentamidine and berenil, were found to abrogate lysis induced by the P2 transport of melarsen oxide in vitro. Furthermore, [ring-3 H]pentamidine transport was blocked by a number of P2 transporter substrates and inhibitors, as well as by other diamidine drugs. Analysis of the uptake of pentamidine and other diamidines in melarsen-resistant trypanosomes in vitro and in vivo, which also show differential levels of resistance to these compounds in vivo, indicated that P2 transport was altered in these cells and that accumulation of these drugs was markedly reduced.

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“…Dicationic-substituted aromatic molecules related to pentamidine have long been known to be effective antiparasitic agents (35). Recent studies have found that a number of direct analogs of pentamidine have activity against Pneumocystis carinii (19), Giardia lamblia (3), Toxoplasma gondii (25), Cryptosporidium parvum (7), Leishmania amazonensis subsp.…”

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confidence: 99%

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells

Dykstra

McClernon

Elwell

et al. 1994

Antimicrob Agents Chemother

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Type I and II topoisomerase activities were partially purified from Pneumocystis carinii. The catalytic (strand-passing) activities of both enzymes were selectively inhibited by members of a series of dicationicsubstituted bis-benzimidazoles compared with those of topoisomerases of mammalian (calf thymus) origin.The most active inhibitors of the parasite enzymes were also highly effective in an in vivo animal model of P.carinii pneumonia. Selected dicationic-substituted bis-benzimidazoles also strongly inhibited the induction of the topoisomerase I-and 11-mediated cleavable complex, suggesting that the biologically active DNA minor groove-binding molecules inhibit the enzyme-DNA binding step of the topoisomerase reaction sequence. The apparent selectivities for the parasite enzymes and the low levels of toxicity to mammalian cells for the biologically active bis-benzimidazoles suggest that these compounds hold promise as effective therapeutic agents in the treatment of a life-threatening AIDS-related disease, P. carinii pneumonia.Dicationic-substituted aromatic molecules related to pentamidine have long been known to be effective antiparasitic agents (35). Recent studies have found that a number of direct analogs of pentamidine have activity against Pneumocystis carinii (19), Giardia lamblia (3), Toxoplasma gondii (25), Cryptosporidium parvum (7), Leishmania amazonensis subsp. mexicana (5), and Plasmodium falciparum (5). A strong correlation was observed between compound activity against G. lamblia in vitro and DNA-binding ability (3). On the basis of those initial results, studies of antiparasitic compounds were extended to a series of compounds with much stronger DNA-binding affinities, the dicationic bis-benzimidazoles. As observed with the pentamidine analogs, a strong correlation was found between DNA binding strength and antigiardial activity for the bisbenzimidazole series [r2 = 0.96 versus calf thymus DNA and i2 = 0.97 versus poly(dA) * (dT)](4). Other studies confirmed that the effective antigiardial compounds were strong DNA minor groove-binding agents with an AT base pair preference (14). Molecular modeling calculations in that study showed that the DNA-binding strength for this class of compound depended on the radius of curvature on the basis of four defined moieties within the molecules, the distance between cationic moieties, the electronic effects from cationic substituents, and hydrogen bonding. There was no evidence of either an intercalative or a covalent interaction of these compounds with nucleic acids. The antigiardiasis study also revealed a convincing correlation between antitopoisomerase II activity and in vitro activity against G. lamblia for the dicationic bis-benzimidazoles (r2 = 0.91) (4). It is unclear whether these compounds manifest their antiparasitic activity primarily by binding to DNA, topoisomerase, or the enzyme-DNA binary complex.As part of a continuing investigation to determine the mechanism of the anti-P. carinii action of these dicationic molecules and to develop new ag...

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The Pharmacology, Mode of Action and Therapeutic Potentialities of Stilbamidine, Pentamidine, Propamidine and Other Aromatic Diamidines—a Review

Cited by 117 publications

References 0 publications

Antifungal and antibacterial activities of diarylamidine derivatives

Antifungal and antibacterial activities of diarylamidine derivatives

Uptake of Diamidine Drugs by the P2 Nucleoside Transporter in Melarsen-sensitive and -resistant Trypanosoma brucei brucei

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells

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