Recent Advances in the Development of Triose Phosphate Isomerase Inhibitors as Antiprotozoal Agents

Abstract

Background: Parasitic diseases caused by protozoa such as Chagas disease, leishmaniasis, malaria, African trypanosomiasis, amebiasis, 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, glycolysis pathway which consists of the conversion of glucose into pyruvate plays an important role in the protozoa energy supply and it is therefore considered as a promising target. In this pathway, triose phosphate isomerase (TIM) plays an essential role in efficient energy production. Furthermore, protozoa TIM show 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 showed mainly 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 were the main pathways that disabled the catalytic activity of the enzyme. Conclusion: Benzothiazole, benzoxazole, benzimidazole, and sulfhydryl derivatives stand out as TIM inhibitors. In silico and in vitro studies demonstrate 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.

Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose

“…). 13 . 2-Amino-5-(4,5-dihydro-1H-imidazol-3-ium-2-yl)benzenethiolate hydrate (1b) (106 mg, 0.50 mmol) and succinic acid (2a) (30 mg, 0.25 mmol) were heated in PPA (8.3 g), and the crude free base was suspended in 2-PrOH (10 mL), and methanesulfonic acid (65 μL, 1.0 mmol) was added and stirred at room temperature for 3 h. After cooling overnight, the resulting precipitate was filtered and dried at 75 °C.…”

“…UPLC (254 nm): 100 area %; MS (ESI): m/z = 224.2 (M + 2H + )/2 calcd for free base 446. 13 (84 mg, 0.5 mmol) and adipic acid (2c) (36 mg, 0.25 mmol) were heated in PPA (8.2 g). The resulting crude free base was suspended in EtOH (10 mL), and methanesulfonic acid (65 μL, 1.0 mmol) was added and stirred at room temperature for 1 h. After cooling overnight, the resulting precipitate was filtered, crystallized from the water/acetone mixture, and dried at 75 °C.…”

“…The resulting crude free base was then suspended in 2-PrOH (10 mL), and methanesulfonic acid (65 μL, 1.0 mmol) was added and stirred at room temperature for 1 h. After cooling overnight, the resulting precipitate was filtered, crystallized from the water/acetone mixture, and dried at 75 °C. 13 . 2-Amino-5-amidiniumbenzenethiolate (1a) (84 mg, 0.5 mmol) and suberic acid (2e) (44 mg, 0.25 mmol) were heated in PPA (10.0 g).…”

“…UPLC (254 nm): 96.0 area %; MS (ESI): m/z = 219.2 (M + 2H + )/2 calcd for free base 436.15. 1 H NMR (300 MHz, DMSO-d 6 ) (δ ppm): 9.21 (br s, 8H, −C(NH 2 ) 2 + ), 8.57 (d, 2H, J = 1.6 Hz, Ar−H), 8.14 (d, 2H, J = 8.6 Hz, Ar−H), 7.86 (dd, 2H, J = 8.6 Hz, J = 1.6 Hz, Ar−H), 3.19 (t, 4H, J = 7.5 Hz, 13 4,5-dihydro-1H-imidazolium-2-yl)benzothiazole Dimethansulfonate (7b). 2-Amino-5-(4,5dihydro-1H-imidazol-3-ium-2-yl)benzenethiolate hydrate (1b) (106 mg, 0.50 mmol) and suberic acid (2e) (44 mg, 0.25 mmol) were heated in PPA (10.6 g).…”

In Vitro and In Silico Analysis of New n-Butyl and Isobutyl Quinoxaline-7-carboxylate 1,4-di-N-oxide Derivatives against Trypanosoma cruzi as Trypanothione Reductase Inhibitors

“…In the last decade, the search for new drugs has focused on pharmacological targets [ 8 ] such as trans -sialidase [ 9 , 10 , 11 , 12 , 13 , 14 ], cruzain [ 15 , 16 , 17 , 18 ], superoxide dismutase [ 19 , 20 ], triose phosphate isomerase [ 7 , 21 ], and trypanothione reductase (TR) [ 5 , 22 , 23 , 24 ]. TR plays a central role in the T. cruzi redox system serving as the enzyme responsible for trypanothione reduction after its oxidation, contributing to oxidative stress relief [ 25 ].…”