Activity of pentamidine and pentamidine analogs against Toxoplasma gondii in cell cultures

Lindsay, David S.; Blagburn, Byron L.; Hall, James Edwin; Tidwell, Richard R.

doi:10.1128/aac.35.9.1914

Cited by 45 publications

(22 citation statements)

References 19 publications

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“…In that study, pentamidine at 25 and 10µg/mL was shown to have significant effects over tachyzoite replication. Lindsay et al 17 obtained a different result from that in the present work, where no anti-Toxoplasma activity of pentamidine was observed at tested concentrations. The conflicting results between these studies may be due to the different cell lines used or differences in methodology because there is no standard model among the authors who perform assays with drugs 17 .…”

Section: Acknowledgmentscontrasting

confidence: 90%

“…More recent studies such as those by Dumas et al 15 and Soheilian et al 16 support the use of this combination to prevent cerebral and ocular toxoplasmosis [14][15][16] . Lindsay et al 17 examined the ability of pentamidine and nine of its analogs to inhibit the replication of RH strain T. gondii in Vero cell cultures. In that study, pentamidine at 25 and 10µg/mL was shown to have significant effects over tachyzoite replication.…”

Section: Acknowledgmentsmentioning

confidence: 99%

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In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii

Gomes

Júnior

Lescano

et al. 2012

Rev. Soc. Bras. Med. Trop.

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Introduction: Toxoplasmosis is usually a benign infection, except in the event of ocular, central nervous system (CNS), or congenital disease and particularly when the patient is immunocompromised. Treatment consists of drugs that frequently cause adverse effects; thus, newer, more effective drugs are needed. In this study, the possible activity of artesunate, a drug successfully being used for the treatment of malaria, on Toxoplasma gondii growth in cell culture is evaluated and compared with the action of drugs that are already being used against this parasite. Methods: LLC-MK2 cells were cultivated in RPMI medium, kept in disposable plastic bottles, and incubated at 36ºC with 5% CO 2 . Tachyzoites of the RH strain were used. The following drugs were tested: artesunate, cotrimoxazole, pentamidine, pyrimethamine, quinine, and trimethoprim. The effects of these drugs on tachyzoites and LLC-MK2 cells were analyzed using nonlinear regression analysis with Prism 3.0 software. Results: Artesunate showed a mean tachyzoite inhibitory concentration (IC 50 ) of 0.075µM and an LLC MK2 toxicity of 2.003µM. Pyrimethamine was effective at an IC 50 of 0.482µM and a toxicity of 11.178µM. Trimethoprim alone was effective against the in vitro parasite. Cotrimoxazole also was effective against the parasite but at higher concentrations than those observed for artesunate and pyrimethamine. Pentamidine and quinine had no inhibitory effect over tachyzoites. Conclusions: Artesunate is proven in vitro to be a useful alternative for the treatment of toxoplasmosis, implying a subsequent in vivo effect and suggesting the mechanism of this drug against the parasite.

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Section: Acknowledgmentscontrasting

confidence: 90%

Section: Acknowledgmentsmentioning

confidence: 99%

In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii

Gomes

Júnior

Lescano

et al. 2012

Rev. Soc. Bras. Med. Trop.

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“…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).…”

mentioning

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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“…[2] Lindsay et al [3] demonstrated the activity of pent-A C H T U N G T R E N N U N G amidine 1 against Toxoplasma gondii in in vitro studies. Furthermore, pentamidine 1 is established in the treatment of Pneumocystis pneumonia (PcP).…”

Section: Introductionmentioning

confidence: 99%

Diacetyldiamidoximeester of Pentamidine, a Prodrug for Treatment of Protozoal Diseases: Synthesis, in vitro and in vivo Biotransformation

et al. 2006

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Pentamidine is an effective antimicrobial agent. To increase its poor oral bioavailability due to the strong basic amidine functionality, the less basic O-acetylamidoxime prodrug, the diacetyldiamidoximeester, was used, which has greatly improved lipophilicity. The objectives of this investigation were the synthesis of all potential metabolites of the double prodrug, the conformational analysis of its structure, and to study the in vitro and in vivo biotransformation by ester cleavage and N-reduction to pentamidine via four intermediate metabolites. The biotransformation of diacetyldiamidoximeester to pentamidine involving the reduction of the amidoxime function and the ester cleavage could be demonstrated. The kinetic parameters were determined. Amidoximes were efficiently metabolized by several enzyme systems located in microsomes and mitochondria of different organs including the final formation of the active metabolite pentamidine. The formation of pentamidine after oral administration of the diacetyldiamidoximeester to rats could be demonstrated as well.

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Activity of pentamidine and pentamidine analogs against Toxoplasma gondii in cell cultures

Cited by 45 publications

References 19 publications

In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii

In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii

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

Diacetyldiamidoximeester of Pentamidine, a Prodrug for Treatment of Protozoal Diseases: Synthesis, in vitro and in vivo Biotransformation

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