Synthesis and Anti-Trypanosoma cruzi Biological Evaluation of Novel 2-Nitropyrrole Derivatives

Human American trypanosomiasis, called Chagas disease, caused by T. cruzi protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-Trypanosoma cruzi derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski’s rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound 3 (CC₅₀ = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC₅₀ = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.     

One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas,X-ray,and In Silico ADME/Tox Profiling Studies

Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.     

Differential pulse voltammetric determination of benznidazole loaded in nanostructured lipid carriers and urine**

Benznidazole (BZN) is the first-choice drug for treating Chagas disease (CD). However, it is not ideal for this purpose as it is highly toxic and has irregular pharmacokinetics due to factors such as its low aqueous solubility. These factors necessitate the development of reliable and effective alternative methods for the analytical determination of BZN in biological and pharmaceutical samples. In this context, we present a new electroanalytical method for quantifying BZN using differential pulse voltammetry (DPV) and a glassy carbon electrode (GCE). This method was applied to urine and a pharmaceutical formulation of BZN incorporated into nanostructured lipid carriers (NLC-BZN). The proposed method provided a linear analytical range of 1.00–10.6 μmol L⁻¹ (R=0.999), with a detection limit of 0.044 μmol L⁻¹ and a quantification limit of 0.13 μmol L⁻¹. The relative standard deviation of the intra-day and inter-day precision was below 2.50 %. Through interference studies, the methodology proved to be selective for BZN, because there was no significant potential interference in any of the samples. The recovery tests showed that the accuracy was within the limits recommended in the literature. Therefore, the developed DPV/GCE method can be successfully applied as an alternative method for detecting BZN in NLC-BZN pharmaceutical formulations and human urine.