Recent synthetic efforts in the preparation of 2-(3,4)-alkenyl (aryl) quinoline molecules towards anti-kinetoplastid agents.

Leishmaniasis, Chagas disease and African sleeping sickness have been considered some of the most important tropical protozoan afflictions. As the number of drugs currently available to treat these human illnesses is severely limited and the majority has poor safety profiles and complicated administration schedules, actually there is an urgent need to develop new effective, safe and cost-effective drugs. Because quinoline alkaloids with antiprotozoal activity (quinine, chimanine, cryptolepine or huperzine groups) were historically and are still essential models for drug research to combat these parasitic infections, synthetic or semi-synthetic quinoline-based molecules are important for anti-kinetoplastid drug design approaches and synthetic methods of their preparation become a key task that is the central subject of this review. Its goal is to highlight the advances in the conventional and current syntheses of new 2-(3,4)-alkenyl (aryl) quinoline derivatives, which kill the most important kinetoplastid protozoa, - Leishmania and Trypanosoma and could be useful models for antileishmanial and antitrypanosomal research. An attempt has been made to present and discuss the more recent contributions in this field over the period 2015-2019, paying special attention to molecular design, synthetic efforts to new green reaction conditions for classical methods such as Skraup synthesis, Friedländer synthesis, Conrad-Limpach, Doebner-Miller, as well as contemporary methods like Gould-Jacobs, Meth-Cohn and Povarov reactions. This review includes brief general information on these neglected tropical diseases, their current chemotherapies, and primary natural models (quinoline alkaloids), suitable for development of anti-kinetoplastid quinoline-based agents. The main part of the review comprises critical discussion on the synthesis and chemistry of new quinolines diversely substituted by alkyl (alkenyl, aryl) fragments on the pyridine part of the quinoline skeleton, which could be considered interesting analogues of chimanine alkaloids. The methods described in this review were developed with the aim of overcoming the drawbacks of the traditional protocols using revolutionary precursors and strategies.

Bioactivity of semisynthetic eugenol derivatives against Spodoptera frugiperda (Lepidoptera: Noctuidae) larvae infesting maize in Colombia.

The anti-acetylcholinesterase, larvicidal, antifeedant activities and general toxicity of 15 semisynthetic eugenol derivatives based on clove oil (including the own oil), were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). Therefore, promising eugenol molecules were classified with larvicidal, anti-acetylcholinesterase and antifeedant activities for controlling this pest. During structure-activity relationship studies and physicochemical profile analysis, it was found that among tested molecules 1-15, eugenol 1, prenyl eugenol 4, isoeugenol 8 and isoeugenol acetate 11 exhibited lethal effects LD50 at concentrations <1 mg/g of insect. On the other hand, eugenol 1, metallyl eugenol 3, isoeugenol 8 and isoeugenol acetate 11 showed a good antifeedant activity (CE50 = 158-209 µg/mL) with a high antifeedant index (70-78%) at concentration 1000 µg/mL, possessing a weak anti-acetylcholinesterase activity (IC50 = 21-31 µg/mL). According to their ecotoxicological profiles (LC50 = 2033.1-6303.8 µg/mL on Artemia salina larvae), isoeugenol 8 and its acetate derivative 11 could be potential used in control of the growth, feeding, or reproduction of S. frugiperda larvae, acting as moderate insecticidal acetylcholinesterase inhibitors and/or antifeedant molecules. Such structure-activity relationship studies could stimulate the identification of lead structures from natural sources for the development of larvicidal and deterrent products against S. frugiperda and related insect pests.

Design, synthesis, acetylcholinesterase inhibition and larvicidal activity of girgensohnine analogs on Aedes aegypti, vector of dengue fever.

Girgensohnine alkaloid was used as a natural model in the design and generation of new alkaloid-like α-aminonitrile series that was completed by the use of SSA-catalyzed Strecker reaction between commercial and inexpensive substituted benzaldehydes, piperidine (pyrrolidine, morpholine and N-methylpiperazine) and acetone cyanohydrin. Calculated ADMETox parameters of the designed analogs revealed their good pharmacokinetic profiles indicating lipophilic characteristics. In vitro AChE enzyme test showed that obtained α-aminonitriles could be considered as AChEIs with micromolar IC50 values ranging from 42.0 to 478.0 µM (10.3-124.0 µg/mL). Among this series, the best AChE inhibitor was the pyrrolidine α-aminonitrile 3 (IC50 = 42 µM), followed by the piperidine α-aminonitriles 2 and 6 (IC50 = 45 µM and IC50 = 51 µM, respectively), and the compound 7 (IC50 = 51 µM). In vivo insecticidal activity of more active AChEIs against Aedes aegypti larvae was also performed showing a good larvicidal activity at concentrations less than 140 ppm, highlighting products 2 and 7 that could serve as lead compounds to develop new potent and selective insecticides.

Cantharidin-based small molecules as potential therapeutic agents.

Chemical and pharmacological information on cantharidin-based small molecules was analyzed. The review summarizes new facts about blister beetles' metabolites for the period 2006-2012. General synthetic approaches to cantharidin-based small molecules as well as their chemical transformations and biological activities related to cantharidin, norcantharidin, cantharidimide, and norcantharimide analogs, especially their inhibitory activity of phosphoprotein phosphatases in cancer treatment, were discussed in this mini review, which could help to design new small molecule modulators for other biological models.

Cytotoxic and Antifungal Activities of Diverse α-Naphthylamine Derivatives.

Diverse α-naphthylamine derivatives were easily prepared from corresponding aldimines derived from commercially available α-naphthaldehyde and anilines or isomeric pyridinecarboxyaldehydes and α-naphthylamine. The secondary amines obtained were tested as possible antifungal and cytotoxic agents. The diverse N-aryl-N-[1-(1-naphthyl)but-3-enyl]amines obtained were active (IC(50) < 10 µg/mL) against breast (MCF-7), non-small cell lung (H-460), and central nervous system (SF-268) human cancer cell lines, while N-(pyridinylmethyl)-naphthalen-1-amines resulted in activity against (MIC 25-32 µg/mL) some human opportunistic pathogenic fungi including yeasts, hialohyphomycetes, and dermatophytes.

Scavenger Activity Evaluation of the Clove Bud Essential Oil (Eugenia caryophyllus) and Eugenol Derivatives Employing ABTS Decolorization.

The essential oil (EO) of clove bud dried fruits from Eugenia caryophyllus was obtained by a conventional hydrodistillation process in an excellent yield (11.7 %). Its chemical composition was analyzed by GC-MS, identifying eugenol as a main constituent (60.5%). Four eugenol-like molecules, γ-diisoeugenol, hydroxymethyleugenol, dihydroeugenol and 1,3-dioxanylphenol, were synthesized using eugenol or isoeugenol as initial precursors under green chemistry protocols. To evaluate the possible antioxidant capacity of eugenol compounds including the clove bud EO, the Trolox® Equivalent Antioxidant Capacity value, obtained by the ABTS(+•) radical-cation discoloration method, was employed. The methodology was performed in a UV-Vis reader of 96-well microplates (dilution methodology), using well-known antioxidant agents (BHA, BHT and vitamin E) as reference compounds. It was found that the prepared eugenol derivatives had a more potent free radical scavenger activity than the reference compounds. In particular, the most active molecules, γ-diisoeugenol and 1,3-dioxanylphenol, were ca. 3-fold more potent than vitamin E.

Challenges and perspectives of chemical biology, a successful multidisciplinary field of natural sciences.

Objects, goals, and main methods as well as perspectives of chemical biology are discussed. This review is focused on the fundamental aspects of this emerging field of life sciences: chemical space, the small molecule library and chemical sensibilization (small molecule microassays).

Antifungal and cytotoxic activities of some N-substituted aniline derivatives bearing a hetaryl fragment.

Diverse N-substituted anilines bearing hetaryl fragments were easily prepared from corresponding aldimines derived from commercially available aromatic aldehydes and anilines. 2-Furyl substituted anilines showed very good antifungal activities against dermatophytes, particularly against Trichophyton rubrum (MIC=3.12-6.25microg/mL). In addition, all active compounds, 45-47, 73, and 74, were tested for cytotoxic activities against breast (MCF-7), lung (H-460), and central nervous system (SF-268) human cancer cell lines with the NCI-anticancer-drug screen. The activity of amines described in this paper, along with the low toxicity of most of them, shows promise for the future development of non-toxic new antimycotic agents.

4,6-Dimethyl-2-(3-pyridyl)quinolin-5-amine.

The title compound, C(16)H(15)N(3), shows a hindrance effect between adjacent amino and methyl groups that leads to a structural distortion, which is reflected in the non-planarity of the quinoline entity and in the bond angles and distances. The crystal packing consists of chains along the b axis sustained by an intermolecular hydrogen bond between the amino group and the N atom of the pyridyl ring.