Pyridine and quinoline molecules as crucial protagonists in the never-stopping discovery of new agents against tuberculosis.

Tuberculosis (TB) disease remains to be an alarming infection worldwide with nearly 1.6 million deaths per year ranking above HIV/AIDS. Although Mycobacterium tuberculosis (Mtb), which causes TB, was identified more than 130 years ago, nowadays only old vaccine (Bacillus Calmette-Guérin vaccine) and classical toxic drugs that are losing its effectiveness are available in clinic practice. Despite enormous efforts in drug research on TB treatment including vaccines and diagnostics investigations, this old contagious, infectious disease is still a major public health problem. The goal of elimination of epidemic TB disease by 2035 will not be achieved without combined strategies based on faster diagnostic tools, effective vaccines and drugs. In the field of TB chemotherapy, novel molecular design of new compounds able to efficiently kill Mtb via a disruption of new diverse biological targets is evidently required. In this sense, pyridine and quinoline compounds stand out as promising molecules against drug-resistant tuberculosis. Indeed, many candidate drugs based on heterocyclic skeletons are currently being tested. Among them, quinoline derivatives like gatifloxacin, moxifloxacin and bedaquiline (sirturo), and pyridine molecules such as sudoterb and agent BRD-8000.3 have been shown to have high potential for more effective treatment of the drug-resistant forms of TB disease. In this work we review the most significant advances in the design of such molecules discussing briefly their physicochemical parameters (descriptors) calculated by available Molinspiration software.

Synthesis, Biological Evaluation and In Silico Computational Studies of 7-Chloro-4-(1H-1,2,3-triazol-1-yl)quinoline Derivatives: Search for New Controlling Agents against Spodoptera frugiperda (Lepidoptera: Noctuidae) Larvae.

The insecticidal and antifeedant activities of five 7-chloro-4-(1H-1,2,3-triazol-1-yl)quinoline derivatives were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). These hybrids were prepared through a copper-catalyzed azide alkyne cycloaddition (CuAAC, known as a click reaction) and displayed larvicidal properties with LD50 values below 3 mg/g insect, and triazolyl-quinoline hybrid 6 showed an LD50 of 0.65 mg/g insect, making it 2-fold less potent than methomyl, which was used as a reference insecticide (LD50 = 0.34 mg/g insect). Compound 4 was the most active antifeedant derivative (CE50 = 162.1 µg/mL) with a good antifeedant index (56-79%) at concentrations of 250-1000 µg/mL. Additionally, triazolyl-quinoline hybrids 4-8 exhibited weak inhibitory activity against commercial acetylcholinesterase from Electrophorus electricus (electric-eel AChE) (IC50 = 27.7 µg/mL) as well as low anti-ChE activity on S. frugiperda larvae homogenate (IC50 = 68.4 µg/mL). Finally, molecular docking simulations suggested that hybrid 7 binds to the catalytic active site (CAS) of this enzyme and around the rim of the enzyme cavity, acting as a mixed (competitive and noncompetitive) inhibitor like methomyl. Triazolyl-quinolines 4-6 and 8 inhibit AChE by binding over the perimeter of the enzyme cavity, functioning as noncompetitive inhibitors. The results described in this work can help to identify lead triazole structures from click chemistry for the development of insecticide and deterrent products against S. frugiperda and related insect pests.

Semisynthetic eugenol derivatives as antifungal agents against dermatophytes of the genus Trichophyton.

PURPOSE: Eugenol, the main component of clove bud essential oil (Eugenia caryophyllus), has been linked to antimicrobial, anti-inflammatory, insecticidal and immunomodulatory properties. The purpose of this study was to evaluate the antifungal and cytotoxic activity of eugenol, the essential oil of Eugenia caryophyllus, and some semisynthetic derivatives of eugenol against dermatophytes of the genus Trichophyton. METHODOLOGY: We evaluated the antifungal effect of the compounds, determining the minimum inhibitory concentrations (MICs) by the microdilution method and the minimum fungicidal concentrations by cultures from the inhibitions. Additionally, the inhibition of the radial growth of the mycelium of the dermatophyte fungi was tested by poisoned substrate. Cytotoxicity was measured by the colorimetric method on Vero cells. RESULTS: All of the eugenol compounds tested exhibited antifungal properties, showing MICs of 62.5-500 µg ml-1 , determined within three dermatophyte species: Trichophyton rubrum, Trichophyton mentagrophytes and Trichophyton tonsurans. Among these derivatives, methyl isoeugenol, at concentrations of 300 and 100 µg ml-1, was found to completely inhibit (100 %) radial growth of the mycelium of all three species after 20 days of treatment. Additionally, phenotypic variations related to the decrease in pigment production of T. rubrum were observed after treatment with O-ethyl and O-butyl isoeugenol derivatives. Meanwhile, all of the tested (iso)eugenol molecules exhibited moderate toxicity in Vero cells [50 % cytotoxic concentration (the concentration required for a 50 % reduction in cell viability; CC50): 54.06-265.18 µg ml-1 ). CONCLUSION: The results suggest that the semisynthetic eugenol derivatives (SEDs) show promising antifungal activity and selectivity against dermatophyte fungi.

Actividad contra Trypanosoma cruzi, Leishmania chagasi y células de mamífero de nuevas N-bencil (2-furilmetil) cinamamidas / Activity against Trypanosoma cruzi, Leishmania chagasi and mammalian cells of new N-benzyl (2-furylmethyl) cinnamamides

Introducción: La quimioterapia contra la leishmaniasis y la enfermedad de Chagas es inefectiva, condición que agrava el problema de salud pública que estas enfermedades tropicales representan. Objetivo: Determinar la actividad de nuevas N-bencil (2-furilmetil) cinamamidas en las formas libres e intracelulares de Leismania chagasi y Trypanosoma cruzi y en células Vero y THP-1. Materiales y métodos: Los parásitos y las células fueron tratados con diferentes concentraciones de los compuestos y su actividad fue determinada microscópicamente y por ensayos de MTT en el caso de los parásitos y células de mamífero, respectivamente. Los resultados de actividad fueron expresados como la concentración que inhibe o destruye 50% o 90% de los parásitos o células. Resultados: Las N-arilalquilamidas 1, 2 y 5 fueron activos en epimastigotes de T. cruzi con actividades entre CI50 3,71-38,81 µM y CI90 entre 50,87-59,87 µM. El compuesto 2 presentó actividad en amastigotes intracelulares de L. chagasi con CI50 77,76 µM. Las amidas preparadas no presentaron toxicidad en células THP-1 y solo el compuesto 4 fue parcialmente tóxico en células Vero (CC50 65,9 ± 5,71 µM). Conclusiones: La baja toxicidad presentada por los compuestos 1, 2 y 5 y la actividad antiparasitaria mostrada soportan el diseño de nuevas moléculas relacionadas para ser evaluadas en sistemas in vitro e in vivo contra estas enfermedades parasitarias.

Introduction: The chemotherapy against leishmaniasis and Chagas disease is ineffective, a condition that is aggravating the public health problem caused by these tropical diseases. Objective: To determine the activity of new N-benzyl(2-furylmethyl) cinnamamides in the free and intracellular forms of Leishmania chagasi and Trypanosoma cruzi and Vero and THP-1 cells. Materials and Methods: The parasites and cells were treated with different concentrations of the compounds and the activity was determined microscopically and MTT assays in the case of parasites and mammalian cells. Antiparasitic activity of tested compounds was expressed as the concentration that inhibits or destroys 50% or 90% of parasites and cells. Results: The N-arylalkylamides 1, 2 and 5 were active against T. cruzi epimastigotes with a range of activities between IC50 3.71-38.81 ìM and IC90 between 50.87-59.87 ìM. The compound 2 was active on intracellular amastigotes of L. chagasi with IC50 77.76 ìM. The tested amides were not toxic to THP-1 cells; just only compound 4 resulted partially toxic on Vero cells (CC50 65.9 ± 5.71 ìM). Conclusions: The low toxicity and the antiparasitic activity showed by the cinnamanide compounds 1, 2 and 5 support the design of new related molecules in order to be evaluated on in vitro and in vivo systems for these parasitic diseases.