Synthesis and Biological Activity of Nitro Heterocycles Analogous to Megazol, a Trypanocidal Lead

Abstract

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.

Synthesis and characterizations of some new tetra thiosemicarbazones and their cyclization reactions; tetra 4-methyl-5-etoxycarbonyl-2,3-dihydro-1,3-thiazole and tetra 2-acetylamino-4-acetyl-4,5-dihydro-1,3,4-thiodiazole derivatives

“…It was reported that the peak was quite specific spectral data [59][60][61][62]. The 13 C-NMR signal of CH=N function of azomethylene and C=C function of compounds 3a-h appeared at 133-147 ppm and 133-135 ppm, respectively.…”

Multiple Spectroscopic and Theoretical Approaches to Study the Interaction between HSA and the Antiparasitic Drugs: Benznidazole, Metronidazole, Nifurtimox and Megazol

“…All spectra were recorded with appropriate background corrections. CD spectra were measured in the 200-260 nm range, at 310 K. Firstly, the spectrum of a free HSA solution (1.00 × 10 -6 M in PBS solution, pH = 7.4) was recorded and then the spectra resulting from the addition of the maximum (6) where θ is the observed CD (in milli-degrees), n is the number of amino acid residues (585 for HSA), 15 l is the path length of the cell (in cm) and C p is the molar concentration of HSA (1.00 × 10 -6 M). The α-helical content of free HSA, as well as bound with BZL, MTZ, NFX and MZ, can be calculated from the molar residual ellipticity (MRE) values at 208 (equation 7) and 222 nm (equation 8):…”

“…5 Subsequently, several structural changes were introduced in MZ, including substitution on the two rings of the basic nucleus, replacement of the thiadiazole by an oxadiazole, replacement of the nitroimidazole part by a nitrofuran or a nitrothiophene, and substitutions on the exocyclic nitrogen atom; however, megazol is still more biologically active than its derivatives. 6,7 Human serum albumin (HSA) is one of the main water soluble proteins in the bloodstream. Among its functions stands out the biodistribution of different classes of drugs and xenobiotics, as well as small, hydrophobic, endogenous and exogenous molecules.…”

Aspectos mecanísticos da bioatividade e toxicidade de nitrocompostos

“…74 Em outro caso, o megazol, agente tripanocida, teve seu desenvolvimento descontinuado devido à toxicidade e mutagenicidade demonstrada em ensaios realizados in vivo. [75][76][77] Ademais, a presença do grupo nitro ligado a anéis aromáticos pode ser relacionada à incidência de efeitos tóxicos causados pela redução in vivo dos compostos nitroaromáticos. 14 A possibilidade de a atividade biológica ser dependente da ligação dos intermediários de nitrorredução ao DNA promove questionamentos sobre o caráter mutagênico e neoplásico dos nitrocompostos.…”