TY - JOUR
T1 - Recent Advances in the Development of Triose Phosphate Isomerase Inhibitors as Antiprotozoal Agents
AU - Vázquez-Jiménez, Lenci K.
AU - Moreno-Herrera, Antonio
AU - Juárez-Saldivar, Alfredo
AU - González-González, Alonzo
AU - Ortiz-Pérez, Eyra
AU - Paz-González, Alma D.
AU - Palos, Isidro
AU - Ramírez-Moreno, Esther
AU - Rivera, Gildardo
N1 - Publisher Copyright:
© 2022 Bentham Science Publishers.
PY - 2022/4
Y1 - 2022/4
N2 - Background: Parasitic diseases caused by protozoa, such as Chagas disease, leishmaniasis, malaria, African trypanosomiasis, amoebiasis, trichomoniasis, and giardiasis, are considered serious public health problems in developing countries. Drug resistance among parasites justifies the search for new therapeutic drugs, and the identification of new targets becomes a valuable approach. In this scenario, the glycolysis pathway, which converts glucose into pyruvate, plays an important role in the protozoa energy supply, and it is therefore considered a promising target. In this pathway, triose phosphate isomerase (TIM) plays an essential role in efficient energy production. Furthermore, protozoa TIM shows structural differences with human enzyme counterparts, suggesting the possibility of obtaining selective inhibitors. Therefore, TIM is considered a valid approach to develop new antiprotozoal agents, inhibiting the glycolysis in the parasite. Objective: In this review, we discuss the drug design strategies, structure-activity relationship, and binding modes of outstanding TIM inhibitors against Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum, Giardia lamblia, Leishmania mexicana, Trichomonas vaginalis, and Entamoeba histolytica. Results: TIM inhibitors have mainly shown aromatic systems and symmetrical structure, where the size and type of heteroatom are important for enzyme inhibition. This inhibition is mainly based on the interaction with i) the interfacial region of TIM inducing changes on the quaternary and tertiary structure or ii) with the TIM catalytic region, the main pathways that disable the catalytic activity of the enzyme. Conclusion: Benzothiazole, benzoxazole, benzimidazole, and sulfhydryl derivatives stand out as TIM inhibitors. In silico and in vitro studies have demonstrated that the inhibitors bind mainly at the TIM dimer interface. In this review, the development of new TIM inhibitors as antiprotozoal drugs is demonstrated as an important pharmaceutical strategy that may lead to new therapies for these ancient parasitic diseases.
AB - Background: Parasitic diseases caused by protozoa, such as Chagas disease, leishmaniasis, malaria, African trypanosomiasis, amoebiasis, trichomoniasis, and giardiasis, are considered serious public health problems in developing countries. Drug resistance among parasites justifies the search for new therapeutic drugs, and the identification of new targets becomes a valuable approach. In this scenario, the glycolysis pathway, which converts glucose into pyruvate, plays an important role in the protozoa energy supply, and it is therefore considered a promising target. In this pathway, triose phosphate isomerase (TIM) plays an essential role in efficient energy production. Furthermore, protozoa TIM shows structural differences with human enzyme counterparts, suggesting the possibility of obtaining selective inhibitors. Therefore, TIM is considered a valid approach to develop new antiprotozoal agents, inhibiting the glycolysis in the parasite. Objective: In this review, we discuss the drug design strategies, structure-activity relationship, and binding modes of outstanding TIM inhibitors against Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum, Giardia lamblia, Leishmania mexicana, Trichomonas vaginalis, and Entamoeba histolytica. Results: TIM inhibitors have mainly shown aromatic systems and symmetrical structure, where the size and type of heteroatom are important for enzyme inhibition. This inhibition is mainly based on the interaction with i) the interfacial region of TIM inducing changes on the quaternary and tertiary structure or ii) with the TIM catalytic region, the main pathways that disable the catalytic activity of the enzyme. Conclusion: Benzothiazole, benzoxazole, benzimidazole, and sulfhydryl derivatives stand out as TIM inhibitors. In silico and in vitro studies have demonstrated that the inhibitors bind mainly at the TIM dimer interface. In this review, the development of new TIM inhibitors as antiprotozoal drugs is demonstrated as an important pharmaceutical strategy that may lead to new therapies for these ancient parasitic diseases.
KW - Antiprotozoal
KW - drugs
KW - inhibitors
KW - molecular docking
KW - parasitic diseases
KW - triose phosphate isomerase
UR - http://www.scopus.com/inward/record.url?scp=85129719341&partnerID=8YFLogxK
U2 - 10.2174/0929867328666210913090928
DO - 10.2174/0929867328666210913090928
M3 - Artículo de revisión
C2 - 34517794
AN - SCOPUS:85129719341
SN - 0929-8673
VL - 29
SP - 2504
EP - 2529
JO - Current Medicinal Chemistry
JF - Current Medicinal Chemistry
IS - 14
ER -