A kinetic study of the nucleophilic addition reactions of 3-cyanomethylidene-2-oxindoline derivatives with cyclic amines (namely: piperidine, morpholine and pyrrolidine) in MeCN solution at 20 °C is reported. The second-order rate constants showed of this process fit nicely the Brönsted equation log k1 = βnuc pKa + C, allowing the determination of the βnuc parameter in the range of 0.63 < βnuc < 0.77 that indicates that the degree of formation of N–C bond in the transition state is more half complete. Moreover, the analysis of the kinetic measurements based on a good linear log k (20 °C) = sN (E + N) free enthalpy relationship are used to assess the electrophilic reactivity in term of E parameter of these series of 2-oxindoline derivatives Michael acceptors. Of major interest is that the estimated E values were established to cover a domain of reactivity of ~3 units of E, ranging from −17.5 for 2-(5-chloro-2-oxindolin-3-ylidene)malononitrile (the most reactive electrophile) to −20.3 for ethyl 2-(5-chloro-1-methyl-2-oxindolin-3-ylidene)-2-cyanoacetate (the least reactive electrophile). The theoretical reactivity indices ω based on the conceptual Density Functional Theory (DFT) explains correctly the experimental electrophilicity E ordering founded in terms of experimental scales.
Thiazoles, thiazolidinones and azetidinones are highly ranked amongst natural and synthetic heterocyclic derivatives due to their great pharmaceutical potential.
New thiazolidinone and azetidinone class of bioactive agents based on 4-(2,7-dichloro-9H-fluoren-4-yl)thiazole moiety have been successfully synthesized. 4-(2,7-dichloro-9H-fluoren-4-yl)thiazol-2-amine was synthesized and allowed to react with various aryl/heteroaryl aldehydes to afford the corresponding Schiff base intermediates. The target thiazolidinone and azetidinone analogues have derived from Schiff bases by their reactions with thioglycolic acid and chloroacetyl chloride, respectively. The newly synthesized compounds were then evaluated for their antimicrobial activity against some multidrug resistant strains and examined for cytotoxic activity against normal lung fibroblast (WI-38), human lung carcinoma (A549), and human breast carcinoma (MDA-MB-231) cell lines to develop a novel class of fluorene-based bioactive agents. The mode of action and the binding interaction of the synthesized compound with the active sites of dihydrofolate reductase enzyme were well identified by fluorescence-activated cell sorting (FACS) analysis and molecular docking study.
Some of the synthesized compounds showed remarkable activity against A-549 and MDA-MB-231 when compared to Taxol, which was used as a reference drug. 2,7-dichloro-9H-fluorene-based azetidinones are more efficient as antimicrobial and anticancer agents compared to dichloro-9H-fluorene-based thiazolidinones derivatives.
Nucleophilic substitution of carbon-leaving groups (CLGs) and base-catalyzed alcohol dehydration reactions are rare in the organic chemistry literature. Herein, we introduce an unprecedented example of a novel reaction that challenges the poor leaving group abilities of both CLGs and hydroxide ions via a concerted transition state, demonstrating E1cBanion step-2/SNAcyl step-1 reaction mechanism interference, displayed by S1 and S2 scaffolds in an alkaline medium (Schemes 5,8). The work offers swift access to C–C bond hydrolysis in the form of ketone α-hydrolytic cleavage under environmentally convenient conditions. Three reaction products were characterized by single-crystal X-ray crystallography, which supported their computed most stable ring conformer structures. Experimental and DFT evidence evoke fast reaction rates (TS1′, ΔG‡ = 26.8 kcal/mol, Scheme 5 and TS5b, ΔG‡ = 14.9 kcal/mol …
Herein, the presented manuscript provides for an extensive spectrofluorimetric method for micro determination of silver ion. This established method based on the use of the three synthesized 2,6-disubstituted pyridine derivatives (R1, R2 and R3) through exploiting their high fluorescence emission property. A noticeable effect on the fluorescence emission of the reagents after chelation with Ag (I) was monitored. Its noteworthy that the sensitivity and stability of this method was increased by using micellar medium. After chelation with Ag(I), the fluorescence emission of the ligands R1 and R2 were effectively quenched in a regular manner by increasing Ag(I) concentration. In contrast, an increase of the fluorescence intensity for reagent R3 after addition of Ag (I) was observed. The solvatochromism for all reagents under investigation was examined in different solvent. Furthermore, the chelation between Ag(I) and the and designed pyridine reagents was assessed spectrophotometrically. The optimum conditions for the most stable complexes which give a high signal difference were explored and well-determined. The linear range for determination of silver ion were determined and found to be 0.18–1.16, 0.06–0.59 and 0.18–1.43 μg mL−1 for R1, R2 and R3, respectively. The statistical analytical parameters such as LOD, LOQ, SD of slope, SD of intercept and RDS were calculated. In addition, the developed methods were efficaciously applied for determination of Ag(I) in some water samples. These selective complexation methods found to be in good precision compared to official and reported method as revealed F-test.
A series of dispiro[indoline-3,2′-pyrrolidine-3′,3″-indolines] was synthesized via a multicomponent polar [3 + 2] cycloaddition (32CA) reaction of isatin derivatives, sarcosine and (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one derivatives. The regio- and stereochemistries of the cycloadducts were established on the basis of one-dimensional (1D) (1H-, 13C-, 13C-CRAPT NMR) and two-dimensional (2D) homonuclear and heteronuclear correlation NMR spectrometry experiments (1H–1H gDQFCOSY, 13C–1H-HSQCAD, 13C–1H-HMBCAD, 1H–1H-ROESYAD). The molecular mechanism and regio- and stereoselectivities of the cycloaddition (CA) reaction have been investigated utilizing a density functional theory (DFT) method and were thoroughly explained based on the transition-state stabilities and global/local electrophilicity/nucleophilicity reactivity indices of the reactants.
In the present work, twenty-four environmentally-sensitive cyanopyridine fluorophores bearing pyrene and/ or fluorene with different para-substituted-phenyl moieties that have been previously designed and synthesized by us are studied in depth for their photophysical properties. Initially, the optical performances of the compounds were investigated by employing UV–visible and fluorescence spectroscopic tools in various aprotic and protic solvents. All the compounds exhibited absorption bands between 310 and 452 nm, and emission bands between 454 and 633 nm. High sensitivity emission spectra with solvents of different polarities were recorded and studied. The fluorescence quantum yield (ϕf) increased in solvents of low polarity and decreased on increasing the polarity of solvents. On the other hand, in case of strong electron donating (–NMe2) and strong electron attracting (–CN) substitution, a pronounced increase in Stokes shifts (up to 252 nm, 14250 cm−1) were recorded. Lippert-Mataga and Reichardts correlations, applied for estimating the variation in dipole moments (Δμ), suggested that the emissive state of designed fluorescence 3-cyanopyridine derivatives is of strong ICT character. The aprotic and protic solvents gave a linear plot for the Stokes shifts in a Lippert–Mataga plot, which appeared as two distinct domains in ET(30) scales indicating the presence of hydrogen bondings. It was observed that for compounds 5b – 8b, with (-NMe2) group on the skeleton of phenyl ring, the Lippert-Mataga and Reichardt–Dimroth’s plots deviated from linearity signifying that 5b – 8b molecules were involved in specific interaction with protic solvents.
The current study describes the synthesis of heterocycles incorporating 2-pyrazoline and 1,3-thiazol-4-one moieties. The cycloaddition of thiosemicarbazide with diverse chalcones afforded N-thiocarbamoyl pyrazolines, which then reacted with chloroacetic acid to yield 2-pyrazolinyl-1,3-thiazol-4(5H)-ones. The active methylene group at position 5 of the synthesized thiazolones increases its reactivity with aromatic aldehydes, forming the arylidene derivatives. The chemical structures of these compounds were determined through spectral and elemental analyses. Additionally, the compounds were assessed for the antibacterial effectiveness against both Gram-positive and Gram-negative bacteria, as well as against specific species of fungi.
A one-pot multicomponent synthesis and application of new imidazopyridazine based N-phenylbenzamides is described. An atom-economical method involving dimethyl phthalate, substituted anilines, and pyridazine-4,5-diamine provided the desired compounds in 120–150 min with 80–85% yield. The reaction was catalyzed with phosphoric acid, and glycerol was used as a safer, greener solvent. Anticancer evaluation against selected cancer cell lines revealed that compound 4e was the most active from the series and exhibited IC50 values below 9.1 µM. Compounds 4h and 4d also displayed good and comparable IC50 values (10.2–12.1 µM). Molecular docking and molecular dynamic studies showed that compound 4e exhibit good binding affinity and stable complex formation with ABL1-kinase protein, respectively. Additional computational predictions such as ADME and drug-likeness demonstrated the potential of the new benzamides as leads for further development.
