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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
Thiacetazone (TCZ) is a moderately water-soluble weak acid (log P 1.75, pKa 5.11–5.72, MW 262.293). It is a synthetic thiosemicarbazone. TCZ is a pro-drug, activated similar to ETM by ethA and targets mycolic acid synthesis, principally the FASII β-hydroxyacyl ACP dehydratase, encoded by the hadABC operon but also other non-essential mycolic acid-modifying enzymes, including cyclopropane mycolic acid synthases (CmaA2 and PcaA) and the mycolic acid methyltransferases (MMA) (MmaA2 and MmaA4).265 It is active only against M. tuberculosis and M. kansasii. Wild-type MIC99s range from 0.125 to 2 μg/mL.85 Spontaneous mutations in ethA or hadABC conferring resistance occur at a rate of approximately 1 in 107.
Autocrine and Paracrine Actions of Prolactin in Uterine Neoplasia
Published in Nagasawa Hiroshi, Prolactin and Lesions in Breast, Uterus, and Prostate, 2020
Jungi Kimura, Teruhiko Tamaya, Hiroji Okada
Estrogen receptor (ER) assay by flow cytometry — Human endometrial adenocarcinoma cell line HHUA was kindly supplied by Dr. Ishiwata. After plating HHUA cells at a density of 4 × 105 cell/plastic dish (25 cm2, Nunc, Denmark) and culture in Ham’s F-12 (Flow Laboratories, Australia), supplemented with 10% fetal bovine serum (FBS, Gibco, U.S.) to attain exponentially growing submonolayer cells, the medium was replaced by FBS-free Ham’s F-12 with or without indicated concentrations of human PRL (Carbiochem, Lot 586009), except one dish where Ham’s F-12 supplemented with 10% FBS was renewed. After 72-hr incubation, dispersed cell suspension was obtained and incubated with 6 × 10-8M 1-(N)-fluoresceinyl estrone thiosemicarbazone (17-FE) alone or with 6 × 10-6M diethylstilbestrol (DES, Sigma, U.S.) at 37°C for 30 min. After washing the cells with PBS, the cells were stained with propidium iodide at 20°C for 20 min followed by rinse with PBS for 20 min. ER levels were measured by flow cytometry (Spectrum III, Ortho, U.S.) on a single-cell basis as described elsewhere.73
Chemical Hybridization Approaches Applied to Natural and Synthetic Compounds for the Discovery of Drugs Active Against Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Elena Petricci, Paolo Governa, Fabrizio Manetti
Among (iso)thiosemicarbazone-furoxan hybrids, 25–27 showed an in vitro antiepimastigote activity toward two parasite strains (Tulahuen 2 strain and Brener clone) comparable to that of reference compounds nifurtimox and benznidazole (Figure 5) (Porcal et al. 2008). Cytotoxicity of 26 and 27 toward J-774 mouse macrophages was low (142 and 400 μM, respectively), with an important selectivity between 21 and 27. Unexpectedly, cruzain, which was predicted to be one of the possible targets of such compounds, was inhibited by 25 and 27 with IC50 values of 78 μM and 43 μM, respectively, thus suggesting that the mechanism of action was not based on the inhibition of this enzyme. Interestingly, ESR spectroscopy showed that 25 and 27 were metabolically instable in parasite microsomes, yielding N-oxide and hydroxyl radical. This result was consistent with the hypothesis that N-oxide moiety could affect the parasite redox system by generating oxidative stress. Structure and activity of (iso)thiosemicarbazone-furoxan hybrids.
Thio- and selenosemicarbazones as antiprotozoal agents against Trypanosoma cruzi and Trichomonas vaginalis
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Alexandra Ibáñez-Escribano, Cristina Fonseca-Berzal, Mónica Martínez-Montiel, Manuel Álvarez-Márquez, María Gómez-Núñez, Manuel Lacueva-Arnedo, Teresa Espinosa-Buitrago, Tania Martín-Pérez, José Antonio Escario, Penélope Merino-Montiel, Sara Montiel-Smith, Alicia Gómez-Barrio, Óscar López, José G. Fernández-Bolaños
As it can be seen, thiosemicarbazides 23 and 31 and thiosemicarbazones 37, 43 and 57 were active on CL-B5 epimastigotes, showing selectivity indexes (SI) ranging from >4.78 to >11.15. According to these results, they were tested on Y strain epimastigotes: three of them displayed slightly lower activity against moderately drug-resistant parasites, and only 23 and 31 showed similar trypanocidal profiles over both DTU TcVI and TcII strains. As depicted in Table 1, none of these molecules triggered toxic effects on mammalian cells, either phagocytic or non-phagocytic (CC50 >256 µM). In fact, previous studies introduce the capability of different series of thiosemicarbazone-based compounds to inhibit epimastigotes growth, proposing the interaction of these molecules with parasite proteases (i.e., cruzipain, one validated target for Chagas disease) as responsible of such an effect19‒21. Improved inhibition of cruzipain (low nanomolar range) was reported22 for the isosteric replacement of sulphur with selenium, what was claimed to be responsible for the antiparasitic activity of such selenosemicarbazones (epimastigotes and intracellular amastigotes).