Molecular structure of 2-Amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazol (Megazol) and related compounds: A concerted study using X-ray crystallography, molecular mechanics, and semiempirical methods
Abstract:A structural study of three nitroimidazoles was carried out using molecular mechanics, semiempirical methods, and X-ray crystallography. Structural features which might account for the high efficiency of 1 (Megazol) as an antiparasitic drug and its opposite, the inactivity of its regiomers 2 and 3 were examined, i.e., coplanarity of the two rings, preferred conformations, and rotational barriers around the pivot bond between the two rings. For the three compounds an antiperiplanar conformation is preferred for… Show more
“…Alternatively, the difference in biological efficacy of 4-substituted derivatives may rely on the change in structure of the compound that no longer would be planar owing to steric interactions between the substituent at position 4 and the nitro group. As we showed previously, the most efficient compound in the series, megazol, has a planar structure, a feature that might be a requirement for delocalization and consequently for the optimized half-life of the nitro radical anion. 1 Bioreduction Routes for Nitro Compounds…”
As part of our efforts to develop new compounds aimed at the therapy of parasitic infections, we synthesized and assayed analogues of a lead compound megazol, 5-(1-methyl-5-nitro-1H-2-imidazolyl)-1,3,4-thiadiazol-2-amine, CAS no. 19622-55-0), in vitro. We first developed a new route for the synthesis of megazol. Subsequently several structural changes were introduced, including substitutions on the two rings of the basic nucleus, replacement of the thiadiazole by an oxadiazole, replacement of the nitroimidazole part by a nitrofurane or a nitrothiophene, and substitutions on the exocyclic nitrogen atom for evaluation of an improved import by the glucose or the purine transporters. Assays of the series of compounds on the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, as either extracellular cells or infected macrophages, indicated that megazol was more active than the derivatives. Megazol was then evaluated on primates infected with Trypanosoma brucei gambiense, including late-stage central nervous system infections in combination with suramin. Full recovery was observed in five monkeys in the study with no relapse of parasitemia within a 2 year follow-up. Because there is a lack of efficacious treatments for sleeping sickness in Africa and Chagas disease in South America, megazol is proposed as a potential alternative. The mutagenicity of this compound is at present being reevaluated, and metabolism is also under investigation prior to possible further developments.
“…Alternatively, the difference in biological efficacy of 4-substituted derivatives may rely on the change in structure of the compound that no longer would be planar owing to steric interactions between the substituent at position 4 and the nitro group. As we showed previously, the most efficient compound in the series, megazol, has a planar structure, a feature that might be a requirement for delocalization and consequently for the optimized half-life of the nitro radical anion. 1 Bioreduction Routes for Nitro Compounds…”
As part of our efforts to develop new compounds aimed at the therapy of parasitic infections, we synthesized and assayed analogues of a lead compound megazol, 5-(1-methyl-5-nitro-1H-2-imidazolyl)-1,3,4-thiadiazol-2-amine, CAS no. 19622-55-0), in vitro. We first developed a new route for the synthesis of megazol. Subsequently several structural changes were introduced, including substitutions on the two rings of the basic nucleus, replacement of the thiadiazole by an oxadiazole, replacement of the nitroimidazole part by a nitrofurane or a nitrothiophene, and substitutions on the exocyclic nitrogen atom for evaluation of an improved import by the glucose or the purine transporters. Assays of the series of compounds on the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, as either extracellular cells or infected macrophages, indicated that megazol was more active than the derivatives. Megazol was then evaluated on primates infected with Trypanosoma brucei gambiense, including late-stage central nervous system infections in combination with suramin. Full recovery was observed in five monkeys in the study with no relapse of parasitemia within a 2 year follow-up. Because there is a lack of efficacious treatments for sleeping sickness in Africa and Chagas disease in South America, megazol is proposed as a potential alternative. The mutagenicity of this compound is at present being reevaluated, and metabolism is also under investigation prior to possible further developments.
“…Substitution at position 4 either abolished or diminished activity against Trypanosomatidae; it could be related to the loss of planarity of the system as previously shown [56]. What is more, an isomer of Megazol with the nitro group at position 4 was inactive something already noticed for other nitroimidazoles [57].…”
Imidazole and benzimidazole systems are presented in a large number of common therapeutics agents. They were widely used in organic and medicinal chemistry, but recently the development of N-oxide derivatives got an improvement from the point of view of its chemical and biological activity. Though we will review recent developments in chemical and biological profiles (as antitumoral, antiparasitic, antiviral and antimicrobial agents) of these heterocycle systems and the corresponding N-oxides.
“…Spigelman et al (1986) suggested that the structure of suramin may disturb cell membrane surfaces and modify the tight junctions of the blood-brain barrier, thereby facilitating the subsequent penetration of the nitroimidazoles. Rameau et al (1996) showed that megazol has a planar structure, thus giving a good opportunity for a stacking complex formation between megazol and suramin, also in vivo. It is therefore tempting to hypothesize that suramin and megazol act synergistically at the level of the blood-brain barrier.…”
SummaryIn human African trypanosomiasis (HAT), the parasites invade the central nervous system (CNS), leading to the development of meningo-encephalitis and an irreversible demyelinating process, which kills the patient unless specific treatment is undertaken. Among the experimental trypanocides, the nitroimidazole derivative megazol alone at optimal doses does not cure late-stage disease tested in mouse models, however the combination of suramin and megazol is able to cure infected mice without CNS involvement. We recently developed an experimental model of HAT with a sharp decrease in both the food intake and the body weight which may constitute an effective index of the early meningo-encephalitic phase. Using this model, we tested this hypothesis by the exclusive effectiveness of a megazol and suramin combination treatment to eliminate CNS trypanosomes. Sprague-Dawley rats were infected with Trypanosoma brucei brucei AnTat 1.1E. Food intake and body weight were measured daily from the day of infection to death. Haematocrite was measured twice a week. Treatment consisted of 20 mg suramin per kg body weight administered intraperitoneally (i.p.) alone, or three daily doses (80 mg/kg) of megazol given per os, or suramin (20 mg/kg, i.p.) followed 24 h later by three daily doses (80 mg/kg) of megazol given per os. Treatment was followed by an increase in daily body weight and food intake similar to those of the control animals, 2 weeks after treatment. The anaemia developed after infection is also cleared as shown by the haematocrite measurements. The rats treated with megazol alone died about 29 days after treatment and those treated with suramin, after about 26 days. Seven months later, no signs of relapse were seen in 10 of 12 rats treated with the therapeutic combination, indicating that this chemotherapy regimen was curative. The results support our previous finding, i.e. the decrease in body weight may constitute a diagnosis index of the early meningo-encephalitic phase.
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