Enol ethers as carbonyl surrogates in a modification of the Povarov synthesis of 3-aryl quinolines and their anti-Toxoplasma activity

Abstract

A novel method for the preparation of 2-carboxyl-3-aryl quinoline derivatives from anilines, ethyl glyoxalate and enol ethers as phenylacetaldehyde surrogates is reported. The three-component coupling reaction occurs rapidly under mild conditions in dichloromethane catalysed by TFA. The method allows a more direct access to 3-aryl quinolines, sidestepping issues encountered with phenylacetaldehyde derivatives. This chemistry was used to prepare quinolines with 3-diarylether functionality that showed low micromolar efficacy (IC50 range: 5-26 μM) against in vitro Toxoplasma gondii coupled with little or no cytotoxicity (TD50≥ 320 μM) towards the host cells.

Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis—A Short Bridge between Two Distant Illnesses

“…Hence, drug repurposing stems as a useful approach for drug development in these parasitic illnesses. In fact, several studies focus on the evaluation of antimalarial compounds on T. gondii and some even focus concomitantly on therapeutics targeting both parasites [27,[29][30][31].…”

“…In addition, the quinoline chemotype offers effective therapeutic solutions for a variety of different diseases, including infections from bacteria, viruses, fungi, parasites, and, in some cases, even in non-infectious illnesses [38]. Quinolines have also been shown to be effective against infections caused by T. gondii, in both acute and chronic phases [29,30,32,[39][40][41][42].…”

Reductive N-Arylethylation of Aromatic Amines and N-Heterocycles with Enol Ethers

“…Prepared from phenothiazine (199 mg, 1.00 mmol) and (E/Z)-1-methoxy-4-(2-methoxyvinyl)benzene 24 Prepared from phenothiazine (199 mg, 1.00 mmol) and (E/Z)-3-(2methoxyvinyl)pyridine 25 (270 mg in 2 portions, 2.00 mmol, 2 equiv) in CH 2 Cl 2 (2.0 mL); reaction time: 20 h, extraction with CH 2 Cl 2 (2 × 80 mL). FCC [R f = 0.5 (hexanes-EtOAc, 19:1)] gave the pure compound 17 as a white solid; yield: 218 mg (0.72 mmol, 72%); mp 94-95 °C; purity (HPLC, method a): >99%; t R = 0.9 min.…”

“…For this purpose we performed N-arylalkylations of phenothiazine to give products 15-18 using appropriate enol ethers bearing 4-(methoxycarbonyl)phenyl, 23 4-methoxyphenyl, 24 3-pyridyl, 25 and 2-thienyl 26 residues. These building blocks are readily available (as mixtures of E and Z isomers) in high yields from the corresponding (hetero)aromatic aldehydes via Wittig olefination with methoxymethyl(triphenylphosphonium) chloride following established protocols.…”

Detailed analytical studies of 1,2,4-triazole derivatized quinoline

“…Many quinoline based drugs such as Captothecine (anticancer) [2] and Cryptolepine (antimalarial) [3] are available in the market. This skeleton also showed a broad spectrum of biological activities including antiasthmatic [4], antidiabetic [5], antibacterial [6], antitoxoplasma [7], antifungal [8] and anti-HIV [9] activities. Due to the presence of nitrogen, the quinoline moieties act as chelating agent as well as a weak base [10].…”