Enhanced Antigiardial Effect of Omeprazole Analog Benzimidazole Compounds.

Beatriz Hernández-Ochoa,Alfonso Méndez-Tenorio,Araceli Santos-Segura,Jaime Marcial-Quino,Roberto Arreguin-Espinosa,Ernesto Calderón-Jaimes,Adrián Sánchez-Carrillo,Miguel Cuevas-Cruz,Luz María Rocha-Ramírez,Edson Jiovany Ramírez-Nava,Saúl Gómez-Manzo

doi:10.3390/molecules25173979

Abstract

Giardiasis is a diarrheal disease that is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; however, failures in drug therapy are common, and have adverse effects and increased resistance of the parasite to the drug, generating the need to find new alternative treatments. In this study, we synthesized a series of 2-mercaptobenzimidazoles that are derivatives of omeprazole, and the chemical structures were confirmed through mass, 1H NMR, and 13C NMR techniques. The in vitro efficacy compounds against Giardia, as well as its effect on the inhibition of triosephosphate isomerase (TPI) recombinant, were investigated, the inactivation assays were performed with 0.2 mg/mL of the enzyme incubating for 2 h at 37 °C in TE buffer, pH 7.4 with increasing concentrations of the compounds. Among the target compounds, H-BZM2, O2N-BZM7, and O2N-BZM9 had greater antigiardial activity (IC50: 36, 14, and 17 µM on trophozoites), and inhibited the TPI enzyme (K2: 2.3, 3.2, and 2.8 M−1 s−1) respectively, loading alterations on the secondary structure, global stability, and tertiary structure of the TPI protein. Finally, we demonstrated that it had low toxicity on Caco-2 and HT29 cells. This finding makes it an attractive potential starting point for new antigiardial drugs.

Highlights

Parasitic infections such as giardiasis are a human health concern worldwide
It has been observed that omeprazole and certain analogs exhibit antigiardial activity, because these compounds act as inhibitors of the glycolytic enzyme triosephosphate isomerase (TPI) of Giardia lamblia by covalent binding of benzimidazole moiety with cysteine residues [17], suggesting that this enzyme could be proposed as a potential drug target in the antigiardial activity of these compounds [12]
Because the compounds and lansoprazole reduce the catalytic activity and alter the secondary structure of the TPI enzyme from G. lamblia, we evaluated the effect on the thermal stability TM of the TPI enzyme after incubation with the three compounds and the lansoprazole, following changes in the circular dichroism (CD) signal at 222 nm measuring the unfolded fraction of the α-helices through a temperature gradient (35–75 ◦ C)

Summary

Introduction

Molecules 2020, 25, 3979 mainly affecting the infant population, with high morbidity and mortality indexes due to the effects of severe diarrhea, invasive infections, malabsorption syndrome, and resultant impairment of growth and development [1] This parasitosis is considered the main cause of epidemic enteritis worldwide, and a re-emerging infectious disease of public health concern [2,3]. Current pharmacological therapies for giardiasis include metronidazole, tinidazole, ornidazole, and secnidazole; these drugs are derived from the nitroimidazole family, while derivatives of the benzimidazole group include albendazole and mebendazole [5,6,7,8] All these drugs have different mechanisms of action, involving distinct targets and downstream metabolic pathways and mechanisms that affect cellular processes in trophozoites, such as proliferation and conversion into infective cysts

Methods

Discussion

Conclusion