Synthesis and anthelmintic activity of novel thiosemicarbazide and 1,2,4-triazole derivatives: In vitro, in vivo, and in silico study.

Autor: Kołodziej P; Laboratory of Diagnostic Parasitology, Chair and Department of Biology and Genetics, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland. Electronic address: przemyslaw.kolodziej@umlub.pl., Wujec M; Chair and Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland., Doligalska M; Department of Parasitology, Faculty of Biology, University of Warsaw, Miecznikowa 1 Street, 02-096 Warsaw, Poland., Makuch-Kocka A; Department of Pharmacology, Faculty of Health Sciences, Medical University of Lublin, Radziwiłłowska 11 Street, 20-080 Lublin, Poland., Khylyuk D; Chair and Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland., Bogucki J; Chair and Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland., Demkowska-Kutrzepa M; Department of Parasitology and Invasive Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka 12 Street, 20-033 Lublin, Poland., Roczeń-Karczmarz M; Department of Parasitology and Invasive Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka 12 Street, 20-033 Lublin, Poland., Studzińska M; Department of Parasitology and Invasive Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka 12 Street, 20-033 Lublin, Poland., Tomczuk K; Department of Parasitology and Invasive Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka 12 Street, 20-033 Lublin, Poland., Kocki M; Chair and Department of Biology and Genetics, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland., Reszka-Kocka P; Chair and Department of Biology and Genetics, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland., Granica S; Microbiota Lab, Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland., Typek R; Department of Chromatography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sklodowska University in Lublin, Marii Curie Sklodowskiej 3 Square, 20-031 Lublin, Poland., Dawidowicz AL; Department of Chromatography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sklodowska University in Lublin, Marii Curie Sklodowskiej 3 Square, 20-031 Lublin, Poland., Kocki J; Department of Clinical Genetics, Faculty of Medicine, Medical University of Lublin, Radziwiłłowska 11 Street, 20-080 Lublin, Poland., Bogucka-Kocka A; Chair and Department of Biology and Genetics, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland.
Jazyk: angličtina
Zdroj: Journal of advanced research [J Adv Res] 2024 Jun; Vol. 60, pp. 57-73. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1016/j.jare.2023.07.004
Abstrakt: Introduction: Intestinal parasitic infections are neglected diseases and, due to the increasing resistance of parasites to available drugs, they pose an increasing therapeutic challenge. Therefore, there is a great need for finding new compounds with antiparasitic activity.
Objectives: In this work, new thiosemicarbazide and 1,2,4-triazole derivatives were synthesized and tested for their anthelmintic activity.
Methods: The synthesis was carried out by classical methods of organic chemistry. Anthelmintic activity tests were carried out in vitro (Rhabditis sp., Haemonchus contortus, Strongylidae sp.) in vivo (Heligmosomoides polygyrus/bakeri), and in silico analysis was performed.
Results: Quinoline-6-carboxylic acid derivative compounds were designed and synthesized. The highest activity in the screening tests in the Rhabditis model was demonstrated by compound II-1 with a methoxyphenyl substituent LC 50  = 0.3 mg/mL. In the next stage of the research, compound II-1 was analyzed in the H. contortus model. The results showed that compound II-1 was active and had ovicidal (percentage of dead eggs > 45 %) and larvicidal (percentage of dead larvae > 75 %) properties. Studies in the Strongylidae sp. model confirmed the ovicidal activity of compound II-1 (percentage of dead eggs ≥ 55 %). In vivo studies conducted in the H. polygyrus/bakeri nematode model showed that the number of nematodes decreased by an average of 30 % under the influence of compound II-1. In silico studies have shown two possible modes of action of compound II-1, i.e. inhibition of tubulin polymerization and SDH. The test compound did not show any systemic toxic effects. Its influence on drug metabolism related to the activity of cytochrome CYP450 enzymes was also investigated.
Conclusion: The results obtained in the in vitro, in vivo, and in silico studies indicate that the test compound can be described as a HIT, which in the future may be used in the treatment of parasitic diseases in humans and animals.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Databáze: MEDLINE
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