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Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones.

ABSTRACT: Background and objectives: Sleeping sickness and malaria alike are insect-borne protozoan diseases that share overlapping endemic areas in sub-Saharan Africa. The causative agent for malaria has developed resistance against all currently deployed anti-malarial agents. In the case of sleeping sickness, the currently deployed therapeutic options are limited in efficacy and activity spectra, and there are very few drug candidates in the development pipeline. Thus, there is a need to search for new drug molecules with a novel mode of actions. Materials and Methods: In the current study, an in vitro screening of a library of tetralone derivatives and related benzocycloalkanones was effected against T. b. brucei and P. falciparum. Results: Several hits with low micromolar activity (0.4-8 µM) against T. b. brucei were identified. Conclusions: The identified hits have a low molecular weight (<280 Da), a low total polar surface area (<50 Å²), and a defined structure activity relationship, which all make them potential starting points for further hit optimization studies.

SUBMITTER: Beteck RM

PROVIDER: S-EPMC6572618 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones.

Beteck Richard M RM Legoabe Lesetja J LJ Isaacs Michelle M Khanye Setshaba D SD Laming Dustin D Hoppe Heinrich C HC

Medicina (Kaunas, Lithuania) 20190524 5

<i>Background and objectives</i>: Sleeping sickness and malaria alike are insect-borne protozoan diseases that share overlapping endemic areas in sub-Saharan Africa. The causative agent for malaria has developed resistance against all currently deployed anti-malarial agents. In the case of sleeping sickness, the currently deployed therapeutic options are limited in efficacy and activity spectra, and there are very few drug candidates in the development pipeline. Thus, there is a need to search f ...[more]

PMID: 31137665

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Project description:BackgroundSeveral quinoline and structurally related antimalarial drugs are associated with cardiovascular side effects, particularly hypotension and electrocardiographic QT interval prolongation. A prolonged QT interval is a sensitive but not specific risk marker for the development of Torsade de Pointes-a potentially lethal polymorphic ventricular tachyarrhythmia. The increasing use of quinoline and structurally related antimalarials in mass treatments to eliminate malaria rapidly highlights the need to review their cardiovascular safety profiles.MethodsThe primary objective of this systematic review was to describe the documented clinical and electrocardiographic cardiovascular side effects of quinine, mefloquine, lumefantrine, piperaquine, halofantrine, chloroquine, sulfadoxine-pyrimethamine, amodiaquine, and primaquine. Trials in healthy subjects or patients with Plasmodium falciparum or P. vivax infection were included if at least two ECGs were conducted during the trial. All trial designs were included except case reports and pooled analyses. Secondary outcomes were the methods adopted by trials for measuring and reporting the QT interval.ResultsData from trials published between 1982 and July 2016 were included. A total of 177 trials met the inclusion criteria. 35,448 participants received quinoline antimalarials in these trials, of which 18,436 participants underwent ECG evaluation. Subjects with co-medication use or comorbidities including cardiovascular disease were excluded from the majority of trials. Dihydroartemisinin-piperaquine was the drug most studied (5083 participants). Despite enormous use over the past 60 years, only 1076, 452, and 150 patients had ECG recordings reported in studies of chloroquine, amodiaquine, and primaquine respectively. Transiently high concentrations of quinine, quinidine, and chloroquine following parenteral administration have all been associated with hypotension, but there were no documented reports of death or syncope attributable to a cardiovascular cause, nor of electrocardiographic recordings of ventricular arrhythmia in these trials. The large volume of missing outcome information and the heterogeneity of ECG interval reporting and measurement methodology did not allow pooled quantitative analysis of QT interval changes.ConclusionsNo serious cardiac adverse effects were recorded in malaria clinical trials of 35,548 participants who received quinoline and structurally related antimalarials with close follow-up including 18,436 individuals who underwent ECG evaluation. While these findings provide further evidence of the rarity of serious cardiovascular events after treatment with these drugs, they also underscore the need for continued strengthening of pharmacovigilance systems for robust detection of rare drug adverse events in real-world populations. A standardised approach to measurement and reporting of ECG data in malaria trials is also needed.Trial registrationPROSPERO CRD42016036678.

Dataset Information

Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones.

Publications

Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones.

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