3-aryl-indolinones derivatives as antiplasmodial agents: synthesis, biological activity and computational analysis.

Malaria is an infectious illness, affecting vulnerable populations in Third World countries. Inspired by natural products, indole alkaloids have been used as a nucleus to design new antimalarial drugs. So, eighteen oxindole derivatives, aza analogues were obtained with moderate to excellent yields. Also, the saturated derivatives of oxindole and aza derivatives via H2/Pd/C reduction were obtained in good yields, leading to racemic mixtures of each compound. Next, the inhibitory activity against P. falciparum of 18 compounds were tested, founding six compounds with IC50 < 20 µM. The most active of these compounds was 8c; however, their unsaturated derivative 7c was inactive. Then, a structure-activity relationship analysis was done, founding that focused LUMO lobe on the specific molecular zone is related to inhibitory activity against P. falciparum. Finally, we found a potential inhibition of lactate dehydrogenase by oxindole derivatives, using molecular docking virtual screening.

Hit-to-lead optimization of novel 2-alkylaminomethylquinoline derivatives as anti-chagas agents.

Chagas disease is one of the main neglected diseases in the world, being endemic in 21 countries of Latin America. This disease has become a global health problem due to migration of infected people non-endemic countries. Even though this disease affects millions of people, only two drugs are approved for its treatment, benznidazole and nifurtimox, and both have several limitations. We have previously reported the synthesis and biological activity against T. cruzi of polysubstituted quinolines analogous to natural products. Herein, we present the synthesis of rationally-based novel analogous of this family of compounds. All the evaluated compounds presented trypanocidal activity. Three of them (6, 7 and 10) stand out for their selectivity indexes. Ethyl 2-((4-benzyl-1,4-diazepan-1-yl)methyl)-6-chloro-4-phenylquinoline-3-carboxylate (compound 10) was found to display anti-parasite activity, presenting the highest selectivity index. Apart from controlling in vivo the parasitemia levels, compound 10 was able to prevent tissue inflammation, a key factor to prevent the progression to chronic chagasic cardiomyopathy. The therapeutic effects of compound 10 are promising and suggest a new possibility to treat this disease.

Microwave-assisted Synthesis of 2-Styrylquinoline-4-carboxylic Acids as Antitubercular Agents.

BACKGROUND: Many 2-substituted quinolines and especially 2-arylvinyl derivatives isolated from plants or prepared by synthesis have been designed from ethnopharmacological studies. OBJECTIVE: In order to explore new aspects of the structure-antituberculosis activity relationship, a series of styrylquinoline derivatives was prepared. METHOD: A series of styrylquinoline derivatives was prepared from quinaldic acid and a variety of arylbenzaldehydes under eco-friendly conditions via Knoevenagel reaction and trifluoroacetic acid (TFA) as catalyst. RESULTS: The products were obtained in short reaction times and good yields and were evaluated for growth inhibitory activity towards Mycobacterium tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA). CONCLUSION: Three compounds had activity under aerobic conditions.

Synthesis and evaluation of 2-(1H-indol-3-yl)-4-phenylquinolines as inhibitors of cholesterol esterase.

A series of 2-(substituted) phenyl and 2-indolyl quinoline derivatives (10a-l) was synthesized by an efficient microwave-assisted, trifluoroacetic acid-catalyzed, solvent-free method. Evaluation of the inhibitory activity led to the identification of two quinoline inhibitors of cholesterol esterase. 2-(1H-Indol-3-yl)-6-nitro-4-phenylquinoline (10l; IC50=1.98µM) was characterized as a mixed-type inhibitor with a pronounced competitive binding mode.

Design, synthesis and evaluation of acridine and fused-quinoline derivatives as potential anti-tuberculosis agents.

The synthesis of twelve acridine and polycyclic acridine derivatives prepared via the Friedländer reaction is described. The one-pot reactions of 2-amino-5-chloro or 5-nitro-benzophenones and a variety of cyclanones and indanones were carried out in a MW oven under TFA catalysis in good yields. The products were designed according natural antituberculosis products and were evaluated for growth inhibitory activity towards Mycobacterium tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA). Three of them underwent additional testings. The cyclopenta[b]quinoline derivative 9 and the acridine derivative 13 showed remarkable MIC values against the rifampin resistant strain. The former exhibited bactericidal activity at 50 µg/mL, its intracellular activity is similar to rifampin and it was not cytotoxic at low concentrations so it can be considered a new lead compound.

Synthesis, trypanocidal activity and molecular modeling studies of 2-alkylaminomethylquinoline derivatives.

Research and development of new drugs effective in the treatment of Trypanosoma cruzi infections are a real need for the 16 million people infected in the Americas. In a previous work, a quinoline derivative substituted by a 2-piperidylmethyl moiety showed to be active against Chagas disease and was considered a lead compound for further optimization. A series of ten analogous derivatives were tested against epimastigotes as a first approach. In view of their promising results, six of them were evaluated against the blood and intracellular replicative forms of the parasite in humans. Among them, compound 12 which possesses a 6-acetamidohexylamino substituent showed remarkable improvement in activity against epimastigotes, trypomastigotes and amastigotes compared with the structure lead, as well as a good selectivity index for the two parasite stages present in humans. In addition, treatment of infected mice with compound 12 induced a significant reduction in parasitemia compared with non-treated mice. Molecular modeling studies were performed by computational methods in order to elucidate the factors determining these experimental bioactivities.