Antiparasitic activity of furanyl N-acylhydrazone derivatives against Trichomonas vaginalis: in vitro and in silico analyses

Abstract

Background: Trichomonas vaginalis is the causative agent of trichomoniasis, which is one of the most common sexually transmitted diseases worldwide. Trichomoniasis has a high incidence and prevalence and is associated with serious complications such as HIV transmission and acquisition, pelvic inflammatory disease and preterm birth. Although trichomoniasis is treated with oral metronidazole (MTZ), the number of strains resistant to this drug is increasing (2.5-9.6%), leading to treatment failure. Therefore, there is an urgent need to find alternative drugs to combat this disease. Methods: Herein, we report the in vitro and in silico analysis of 12 furanyl N-acylhydrazone derivatives (PFUR 4, a-k) against Trichomonas vaginalis. Trichomonas vaginalis ATCC 30236 isolate was treated with seven concentrations of these compounds to determine the minimum inhibitory concentration (MIC) and 50% inhibitory concentration (IC 50). In addition, compounds that displayed anti-T. vaginalis activity were analyzed using thiobarbituric acid reactive substances (TBARS) assay and molecular docking. Cytotoxicity analysis was also performed in CHO-K1 cells. Results: The compounds PFUR 4a and 4b, at 6.25 µM, induced complete parasite death after 24 h of exposure with IC 50 of 1.69 µM and 1.98 µM, respectively. The results showed that lipid peroxidation is not involved in parasite death. Molecular docking studies predicted strong interactions of PFUR 4a and 4b with T. vaginalis enzymes, purine nucleoside phosphorylase, and lactate dehydrogenase, while only PFUR 4b interacted in silico with thioredoxin reductase and methionine gamma-lyase. PFUR 4a and 4b led to a growth inhibition (< 20%) in CHO-K1 cells that was comparable to the drug of choice, with a promising selectivity index (> 7.4). Conclusions: Our results showed that PFUR 4a and 4b are promising molecules that can be used for the development of new trichomonacidal agents for T. vaginalis.

Novel Treatment Approaches to Combat Trichomoniasis, a Neglected and Sexually Transmitted Infection Caused by Trichomonas vaginalis: Translational Perspectives

“…Diamine 4 presented a MIC value of 70 µM and caused trophozoites death by competition with the spermine transporter [42]. Through in silico analysis, thioredoxin reductase and methionine gamma-lyase were described as targets of the two furanyl N-acylhydrazone derivatives (PFUR) 4a and 4b, presenting IC 50 values of 1.69 µM and 1.98 µM, respectively [45]. After the high-throughput virtual molecular docking of the molecule screening library ChemBridge, the protein triosephosphate isomerase was defined as the target of three compounds, denominated as A5 [35].…”

The Current Directions of Searching for Antiparasitic Drugs

“…The results of in vitro tests against resistant and susceptible parasites may be the starting point for the synthesis of further indazole analogs [59]. In 2020, Alves et al published the results of in vitro and in silico activity stud 12 derivatives of furan-2-yl-N-acylhydrazone (PFUR) against Trichomonas vaginali ure 10) [60]. Due to the increasing resistance to metronidazole, there is a need to for new compounds effective against the above parasite.…”

“…Among the remaining 10 compounds, PFUR 4a and 4b a tinguished by the presence of a nitro group in the heterocyclic ring. Thus, it was that by introducing a nitro group, it is possible to increase the antiparasitic activity a In 2020, Alves et al published the results of in vitro and in silico activity studies of 12 derivatives of furan-2-yl-N-acylhydrazone (PFUR) against Trichomonas vaginalis (Figure 10) [60]. Due to the increasing resistance to metronidazole, there is a need to search for new compounds effective against the above parasite.…”

“…olecules 2022, 27, x FOR PEER REVIEW 13 of 26 [60]. Due to the increasing resistance to metronidazole, there is a need to search for new compounds effective against the above parasite.…”

“…Among the remaining 10 compounds, PFUR 4a and 4b are distinguished by the presence of a nitro group in the heterocyclic ring. Thus, it was found that by introducing a nitro group, it is possible to increase the antiparasitic activity against protozoa [60]. In silico studies have shown that PFUR 4a and 4b have high antiparasitic potential.…”