New Drug Developments for Opportunistic Infections in Immunosuppressed Patients: Pneumocystis carinii

Queener, Sherry F.

doi:10.1021/jm00024a001

Cited by 65 publications

(66 citation statements)

References 83 publications

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“…Because pentamidine and related compounds were shown to bind to the minor groove of the DNA molecule, it was initially thought that the anti-P. carinii properties were reliant upon inhibition of the organism's topoisomerase I (13,28). This was not found to be the case, and later studies with recombinant P. carinii topoisomerase I as a reagent rather than semipurified extracts provided further evidence that the cytotoxic mechanisms of pentamidine were not targeted to this enzyme (35).…”

Section: Discussionmentioning

confidence: 99%

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Cushion

Walzer

Collins

et al. 2004

Antimicrob Agents Chemother

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Trimethoprim-sulfamethoxazole and pentamidine isethionate have been used extensively for the prophylaxis and therapy of pneumonia caused by Pneumocystis jirovecii. Problems associated with toxicity and potential emerging resistance for both therapies necessitate the development of safe and effective analogs or new treatment strategies. In the present study, a library of 36 compounds was synthesized by using the pentamidine molecule as the parent compound modified by a 1,4-piperazinediyl moiety as the central linker to restrict conformation flexibility. The compounds were evaluated for anti-Pneumocystis carinii activity in a bioluminescent ATP-driven assay. Four of the compounds were highly active, with 50% inhibitory concentration (IC 50 ) values of <0.01 g/ml; four had very marked activity (IC 50 < 0.10 g/ml); ten had marked activity (IC 50 < 1.0 g/ml); nine had moderate activity (IC 50 < 10 g/ml); one had slight activity (IC 50 ‫؍‬ 34.1 g/ml); and the remaining eight did not demonstrate activity in this assay system. The high level of activity was specifically associated with an alkyl chain length of five to six carbons attached to one of the nitrogens of the bisamidinium groups. None of the highly active compounds and only one of the very marked compounds exhibited any toxicity when evaluated in three mammalian cell lines. The strategy of substitution of 1,4-piperazine-linked bisbenzamidines produced compounds with the highest level of activity observed in the ATP assay and holds great promise for the development of efficacious anti-P. carinii therapy.Despite advances in the treatment of human immunodeficiency virus infection, Pneumocystis jirovecii pneumonia remains a leading cause of opportunistic infection and mortality in human immunodeficiency virus-infected patients. Currently available anti-Pneumocystis drugs are limited by significant problems of efficacy, toxicity, and emerging resistance (14,21,37,38). No member of the genus Pneumocystis can be maintained continuously outside the mammalian lung. Thus, drug development, as well as other aspects of investigation of this organism family, has been hindered.The effective use of pentamidine isethionate for the treatment of human Pneumocystis pneumonia was first reported in 1958 (18), and the early experience with the drug was summarized in 1967 (19). Trimethoprim-sulfamethoxazole (TMP-SMZ) later became the therapy of choice for this pneumonia due to increased efficacy and reduced toxicity (16). Despite concerted efforts focusing on modifications of the dihydrofolate reductase and dihydropteroate inhibitor portions of TMP-SMZ and the diamidine structure of pentamidine, no compound with increased anti-Pneumocystis carinii properties without toxicity has emerged as a clinical drug (11). With the potential problem of emerging resistance to the sulfa component of TMP-SMZ (1, 21, 26), the significant failure rate of prophylactic pentamidine, and its limited spectrum (17) and associated toxicity (2), it is necessary to identify new therapies or modifications of ...

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Section: Discussionmentioning

confidence: 99%

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Cushion

Walzer

Collins

et al. 2004

Antimicrob Agents Chemother

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“…PQ interferes with the microbial electron transport system by yielding quinone metabolites that generate superoxides in vivo [40]. The PQ-CM approach is employed for the treatment of moderate PCP or as salvage therapy [42][43][44][45][46][47][48][49].…”

Section: Against Pneumocystic Pneumoniamentioning

confidence: 99%

“…The effective daily dose for PCP treatment is 2 mg/kg of PQ and 225 mg/kg of CM. Lower doses are applied for prophylaxis [40].…”

Section: Against Pneumocystic Pneumoniamentioning

confidence: 99%

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

322

308

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“…8,9 However, emerging resistance and allergic reactions against the sulfa component often lead to the alternative use of pentamidine and atovaquone. [8][9][10] Unfortunately, pentamidine is ineffective orally and toxic effects have been reported for this drug, 8 while failure of atovaquone treatment in AIDS patients with PCP is a major concern.…”

mentioning

confidence: 99%

“…9 Optimization of 8-aminoquinolines to improve their antimalarial activity as well as to reduce adverse effects such as neutropenia and methemogobinemia also resulted in an improvement of activity against PCP. 8,12,13 This observation led to the suggestion that such synchrony between the structure-activity relationships (SARs) for the protozoal and fungal diseases could be useful to develop novel 8-aminoquinolines with improved efficacy against PCP (e.g., 1b, c). 14 We recently reported that imidazolidin-4-one derivatives of primaquine, 2 (Scheme 1), exert potent gametocytocidal activity against Plasmodium berghei infection developed in BalbC mice.…”

mentioning

confidence: 99%

Anti-Pneumocystis carinii and antiplasmodial activities of primaquine-derived imidazolidin-4-ones

Vale

Collins

Gut

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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Abstract-A series of primaquine-derived imidazolidin-4-ones were screened for their in vitro activity against Pneumocystis carinii and Plasmodium falciparum W2 strain. Most compounds were active against P. carinii above 10 lg/mL and displayed slight to marked activity. The imidazolidin-4-ones most active against P. carinii were also those most active antiplasmodial agents, in the lM range. One of the tested imidazolidin-4-ones was slightly more active than the parent primaquine and may represent a lead compound for the development of novel anti-P. carinii 8-aminoquinolines with increased stability and resistance to metabolic inactivation.

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New Drug Developments for Opportunistic Infections in Immunosuppressed Patients: Pneumocystis carinii

Cited by 65 publications

References 83 publications

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Primaquine revisited six decades after its discovery

Anti-Pneumocystis carinii and antiplasmodial activities of primaquine-derived imidazolidin-4-ones

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