Effects of SQ109 on Trichomonas vaginalis

Trichomonas vaginalis is a parasite that causes human trichomoniasis, the most prevalent non-viral sexually transmitted infection (STI) on the planet, affecting approximately 278 million people worldwide (Kreisel et al., 2021). Pregnant women with trichomoniasis may experience miscarriage, premature delivery, premature rupture of the placenta, and pregnancy disorders (Petrin et al., 1998). The disease can also cause infertility (Lewis, 2010; Mielczarek and Blaszkowska, 2016). In men, the disease is usually asymptomatic. However, in more severe cases, inflammation of the urethra and prostate may be present (Rein, 1990). T. vaginalis infection is also related to a predisposition to infections caused by the human immunodeficiency virus (HIV) (Van Der Pol et al., 2008), human papillomavirus (HPV) (Noël et al., 2010), and cervical cancer of the uterus and prostate (Sutcliffe et al., 2006).

The current treatment for human trichomoniasis consists of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, the Metronidazole (MTZ). It is a compound widely used to treat infections caused by bacteria (Helicobacter, Bacteroides, and Clostridium) and anaerobic parasites such as Trichomonas, Entamoeba, and Giardia (Edwards, 1993). Although effective in eradicating most parasitic infections, this drug is related to serious adverse effects such as nausea, vomiting, dizziness, metallic taste, and insomnia (De Andrade Rosa et al., 2011). Furthermore, it can cause pancreatitis, leukopenia, and neuropathies in the most severe cases. Furthermore, this therapy cannot be used during pregnancy (Lossick, 1990). In addition to treatment toxicity, some strains have become resistant to 5′-nitroimidazoles (Paulish-Miller et al., 2014).

Several compounds have been tested against protozoa parasites; among them, Miltefosine, Methyl jasmonate, Δ(24(25))-sterol methyltransferase inhibitors, 3-(biphenyl-4-yl)-3-hydoxyquinuclidine (BPQ-OH), Lactacystin, Zinc-clotrimazole complexes, Amiodarone, Amioder, Dronedarone, Thiosemicarbazones 49, 51, and 63, selenoisosters 74 and 75, β-Lapachone, BPQ-OH, drugs such as Ixazomib and carmaphycin-17, exhibited effects on the growth curve and affected cell organelles of the parasites (reviewed by Benchimol et al., 2022). In addition to nitroimidazoles, articles describe promising plant-based compounds with anti-trichomonal activity in vitro and in vivo (Hashemi et al., 2021). However, in-depth in vivo evaluation of the compounds and their clinical evaluation has not been performed. Other studies provided an overview of clinically evaluated systemic and topical treatment options for human trichomoniasis. Furthermore, they summarized the current knowledge on herbal, semisynthetic, and synthetic compounds evaluated for efficacy as anti-Trichomonas (Küng et al., 2019). Therefore, developing new alternative drugs for trichomoniasis is necessary and urgent. SQ109[N-adamantan-2-yl-N'-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2 diamine] is an antitubercular drug candidate that completed Phase IIb/III clinical (Baek et al., 2022). It has been reported that SQ109 has in vitro activity against the parasite Trypanosoma cruzi, the causative agent of Chagas disease (Veiga-Santos et al., 2015), where this compound inhibited the proliferation of intracellular amastigotes as well as epimastigotes forms. Furthermore, SQ109 provoked major ultrastructural changes in the three life cycle forms of this parasite (Veiga-Santos et al., 2015). SQ109 also inhibited the growth of the amastigote form of Leishmania mexicana with a good selectivity index. In addition, it was also active against promastigotes, disturbing Ca2+ homeostasis (García-García et al., 2016). SQ109 also effectively inhibited the proliferation of Leishmania donovani, the parasite responsible for visceral leishmaniasis, exhibiting a toxic effect on amastigotes. It was demonstrated that SQ109 induced rapid damage in acidocalcisomes (Gil et al., 2020), organelles involved in many important functions, including Ca2+ homeostasis. The compound significantly increased intracellular Ca2+ concentration, causing the parasite's death (Gil et al., 2020). The present work describes results obtained using SQ109 in T. vaginalis.

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