Brain‐Penetrant Triazolopyrimidine and Phenylpyrimidine Microtubule Stabilizers as Potential Leads to Treat Human African Trypanosomiasis

Monti, Ludovica; Wang, Steven C; Oukoloff, Killian; Smith, Amos B.; Brunden, Kurt R.; Caffrey, Conor R.; Ballatore, Carlo

doi:10.1002/cmdc.201800404

Cited by 23 publications

(35 citation statements)

References 33 publications

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“…Trypanosoma brucei. The SYBR Green assay ( [80] as modified by Monti et al [81]) was employed to measure the effect of test compounds on cell viability. Compounds in 100% DMSO stocks were diluted in 100μL HMI-10 modified medium in 96-well plates (Corning 3903) such that the final DMSO concentration was 0.5%.…”

Section: Parasite Drug Susceptibility Testingmentioning

confidence: 99%

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

Ehrenkaufer

Stebbins

et al. 2020

PLoS Negl Trop Dis

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Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the PLOS NEGLECTED TROPICAL DISEASES

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Section: Parasite Drug Susceptibility Testingmentioning

confidence: 99%

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

Ehrenkaufer

Stebbins

et al. 2020

PLoS Negl Trop Dis

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“…To this effect, we cross screened a library of 2-quinazolinone compounds previously reported as monoamine oxidase inhibitors [39] for antitrypanosomal activity. Cross screening is a cost-effective approach for hit and lead generation [40][41][42]. The compounds were screened against T.b.…”

Section: Introductionmentioning

confidence: 99%

In-vitro Anti-trypanosomal and Cytotoxicity Evaluation of 3-methyl-3,4-dihydroquinazolin-2(1H)-one Derivatives

2021

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Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein current treatments suffer from several drawbacks such as toxicity, low activity, and poor pharmacokinetic properties, and hence the need for alternative treatment is apparent. To this effect, we screened in vitro a library of 2-quinazolinone derivatives for antitrypanosomal activity against T.b. brucei and cytotoxicity against HeLa cells. Seven compounds having no overt cytotoxicity against HeLa cells exhibited antitrypanosomal activity in the range of 0.093–45 µM were identified. The activity data suggests that the antitrypanosomal activity of this compound class is amenable to substituents at N1 and C6 positions. Compound 14 having a molecular weight of 238Da, ClogP value of 1 and a total polar surface area of 49 was identified as the most active, exhibiting an IC50 value of 0.093 µM Graphical Abstract.

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“…In light of the relatively small/simple structure, the generally favorable physicochemical properties, as well as the tunable mode of action, MT-active TP derivatives have been proposed as potential treatments for diseases of the CNS. [99][100][101] Interestingly, although 67 was found to have rather limited brain penetration as revealed by a brain-to-plasma ratio (B/P) of approximately 0.03 at 1h post i.p. administration in mice, several closely related congeners exhibit excellent brain exposure.…”

Section: 24-triazolo[15-a]pyrimidines In Anti-cancer Agentsmentioning

confidence: 99%

1,2,4-Triazolo[1,5-a]pyrimidines in drug design

Oukoloff

Lucero

Francisco

et al. 2019

European Journal of Medicinal Chemistry

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The 1,2,4-triazolo [1,5-a]pyrimidine (TP) heterocycle, in spite of its relatively simple structure, has proved to be remarkably versatile as evidenced by the many different applications reported over the years in different areas of drug design. For example, as the ring system of TPs is isoelectronic with that of purines, this heterocycle has been proposed as a possible surrogate of the purine ring. However, depending on the choice of substituents, the TP ring has also been described as a potentially viable bio-isostere of the carboxylic acid functional group and of the N-acetyl fragment of ε-N-acetylated lysine. In addition, the metal-chelating properties of the TP ring have also been exploited to generate candidate treatments for cancer and parasitic diseases. In the present review article, we discuss recent applications of the TP scaffold in medicinal chemistry, and provide an overview of its properties and methods of synthesis.

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Brain‐Penetrant Triazolopyrimidine and Phenylpyrimidine Microtubule Stabilizers as Potential Leads to Treat Human African Trypanosomiasis

Cited by 23 publications

References 33 publications

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

In-vitro Anti-trypanosomal and Cytotoxicity Evaluation of 3-methyl-3,4-dihydroquinazolin-2(1H)-one Derivatives

1,2,4-Triazolo[1,5-a]pyrimidines in drug design

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