Ultrasonic-induced synthesis of novel diverse arylidenes via Knoevenagel condensation reaction. Antitumor, QSAR, docking and DFT assessment.

A series of arylidenes derivatives was synthesized under ultrasonic methodology via Knoevenagel condensation reaction of cyanoacetohydrazide derivative with the appropriate aldehydes and/or ketone. The anticancer properties of the newly synthesized compounds were tested against four different human cancer cell lines (HEPG-2, MCF-7, HCT-116, and PC-3); compounds 5d and 6 demonstrated the greatest anticancer activity against all cancer cell lines. The MLR technique was used to create the QSAR model using five molecular descriptors (AATS6p, AATS7p, AATS8p, AATS0i, and SpMax4_Bhv). The examination of the constructed QSAR model equations revealed that the selected descriptors influence the tested compound's anti-proliferative activity. The descriptors identified in this work by QSAR models can be utilized to predict the anticancer activity levels of novel arylidenes derivatives. This will allow for significant cost savings in the drug development process and synthesis at pharmaceutical chemistry laboratories. According to the physicochemical properties, the results revealed that all of these compounds comply with Lipinski's Rule of Five, indicating that they may have high permeability across biological membranes and reveal drug-relevant properties. The Swiss Target Prediction webtool was used to assess the probable cellular mechanism for the promising candidate compounds (5d and 6), and the results revealed that adenosine A1 receptor (ADORA1) was a common target for both compounds. ADORA1 is involved in the regulation of cell metabolism and gene transcription. ADORA1 overexpression has been linked to a variety of cancers, including colon cancer, breast cancer, leukemia, and melanoma. The docking study of tested compounds 5d and 6 revealed that their binding scores to ADORA1 are more favorable than those of its co-crystalized ligand (DU172, selective ADORA1 antagonist) and adenosine (ADORA1 endogenous agonist), implying that they may hold great promise as an anti-cancer therapy. Density functional theory (DFT) with a (B3LYP)/6-31G (d,p) basis set was used to calculate the physicochemical parameters of these compounds. The theoretical data from the DFT computation was found to be in good agreement with the experimental values.

Synthesis, antimicrobial activities, docking studies and computational calculations of new bis-1,4-phenylene -1H-1,2,3-triazole derivatives utilized ultrasonic energy.

In this elucidation, we studied the utility of condensation reaction between 1,4-phenylenediamine (1) with acetyl acetone (2) with hydrazine hydrate utilized ultrasonic energy in one step reaction to afford the corresponding 1,1'-(1,4-phenylenebis (5-methyl-1H-1,2,3-triazole-1,4-diyl))bis(ethan-1-one) (4) in excellent yield. The ethanol solution of bis triazole (4) and different aldehyde derivatives were sonicated at 75 °C for 2 h to afford chalcone derivatives 5a-d which were confirmed via spectral data such as FTIR, 1HNMR, 13CNMR and mass spectra. Moreover, the intermolecular cyclization of chalcone (5a) with NH2NH2 in sodium hydroxide solution to give the corresponding 4,5-dihydro-1H-pyrazol-5-yl)-1H-indole (6) using ultrasonic energy for 4 h, while the Michael addition of chalcones (5a) and (5 b) with thiourea in basic condition to afford the corresponding pyrimidine-2-thiol derivatives (7) and (9). Treatment of compound (7) with NH2NH2 to afford 1,4-bis(4-(2-hydrazineyl-6-(1H-indol-3-yl)pyrimidin-4-yl) derivatives (8). The synthesized compounds were screened against various microbial strains and displayed excellent antimicrobial potential. Additionally, the docking studies of these nine compounds were carried out with (PDB ID:3t88), (PDB ID:2wje), (PDB ID:4ynt) and (PDB ID:1tgh) which were attached with different amino acids with shortage bond length, and it was noticed that PMTS1, PMTS2 and PMTS3 were the most stable compounds with the lowest energy affinity which is compatible with biological study. Furthermore, the theoretical investigation of bis-triazole compounds were optimized via DFT/B3LYP/6-31G(d) level which showed the hyperconjugation of nitrogen atoms and elucidated their physical parameters and NBO charges and confirmed their stability and biological activity.Communicated by Ramaswamy H. Sarma.

Synthesis, in Vivo Anti-inflammatory, and in Vitro Antimicrobial Activity of New 5-Benzofuranyl Fused Pyrimidines.

Chalcone (3) has been synthesized as a new chalcone derivative bearing benzofuran moiety at 1 position. Such chalcone was used as a model dielectrophile applied to react with some nucleophiles such as 5-amino pyrazoles, 5-amino-1,2,4-triazole, 2-aminobenzimidazole, and 6-uraciles under Michael reaction conditions and resulted in a new series of fused pyrimidines such as pyrazolo[1,5-a]pyrimidines 7a-e, [1,2,4]-triazolo[1,5-a]pyrimidine 9, pyrimido[1,2-a]benzimidazole 11, and synthesis of pyrido[2,3-d]pyrimidinones 13a and b. The structures of the synthesized target heterocyclic compounds were confirmed by microanalytical and spectral data such as Fourier transform (FT)-IR, (1)H-NMR, and MS spectra. The newly synthesized compounds were evaluated for their anti-inflammatory and antimicrobial activities; most showed significant activities.

Synthesis and Some Reactions of 1-aryl-4-acetyl-5-methyl-1,2,3-triazole Derivatives with Anticonvulsant Activity.

The triazoles 3a-d underwent condensation reactions with 4-(piperidin-1-yl)-benzaldehyde to afford the chalcones 5a-d. Chalcone derivatives 5a-d were reacted with 2,3-diaminomaleonitrile, thiourea and hydrazine hydrate to afford the novel diazepine-dicarbonitrile derivatives 7a-d, the pyrimidine-2-thiol derivatives 9a-d and hydrazino-pyrimidines 10a-d respectively. Structures of the prepared compounds were elucidated by physical and spectral data like FT-IR, (1)H NMR, (13)C NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their anticonvulsant activity and SAR.

Experimental and theoretical study of the [3 + 2] cycloaddition of carbonyl ylides with alkynes.

The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and alkynes (phenylacetylene, methyl propiolate, methyl but-2-ynoate and methyl 3-phenylpropiolate) to give substituted 2,5-dihydrofurans was investigated. The effect of indium(III) chloride on the outcome of the reaction was studied in the case of phenylacetylene and methyl propiolate. The thermal reaction between the carbonyl ylide coming from 2,2-dicyano-3-phenyloxirane and both methyl propiolate and methyl but-2-ynoate was theoretically investigated using DFT methods in order to explain the reactivity and regioselectivity observed.

Synthesis of Diarylpyrazoles Containing a Phenylsulphone or Carbonitrile Moiety and their Chalcones as Possible Anti-Inflammatory Agents.

A series of chalcone-based diarylpyrazoles containing a phenylsulphone or carbonitrile moiety was synthesized. Thus, 3-acetylpyrazoles 6a-c and 10a-c were used as useful substrates in facile synthesis of functional pyrazoles 7a-f and 11a-f, respectively. The anti-inflammatory activity and ulcerogenic effect were evaluated and some of the obtained products possessed a significant anti-inflammatory activity. 1-[1-(3-Methylphenyl)-5-phenyl-4-(phenylsulfonyl)-1H-pyrazol-3-yl]ethanone (6b) showed a high activity when compared with indomethacin as reference drug with lower gastrointestinal (GI) profile. Furthermore, molecular docking studies were performed in order to rationalize the obtained biological results.

A combined experimental and theoretical study of the thermal cycloaddition of aryl azides with activated alkenes.

Reactions were performed from aryl azides on the one hand, and activated alkenes coming from ß-dicarbonyl compounds or malonodinitrile on the other hand, either with recourse to conventional heating or to microwave activation, to afford 1-aryl-1H-1,2,3-triazoles. The mechanism and the regioselectivity of the reactions involving ß-dicarbonyl compounds have been theoretically studied using DFT methods at the B3LYP/6-31G* level: they are domino processes comprising a tautomeric equilibrium of the ß-dicarbonyl compounds with their enol forms, a 1,3-dipolar cycloaddition of the enol forms with the aryl azides (high activation energy), and a dehydration process (lower activation energy). The effect of non-conventional activation methods on the degradation of 1,2,3-triazolines was next studied experimentally. Finally, some of the 1,2,3-triazoles such synthesized were evaluated for their bactericidal and cytotoxic activities.

Direct metalation of heteroaromatic esters and nitriles using a mixed lithium-cadmium base. Subsequent conversion to dipyridopyrimidinones.

All pyridine nitriles and esters were metalated at the position next to the directing group using (TMP)(3)CdLi in tetrahydrofuran at room temperature. The 2-, 3-, and 4-cyanopyridines were treated with 0.5 equiv of base for 2 h to afford, after subsequent trapping with iodine, the corresponding 3-iodo, 2-iodo, and 3-iodo derivatives, respectively, in yields ranging from 30 to 61%. Cyanopyrazine was similarly functionalized at the 3 position in 43% yield. Ethyl 3-iodopicolinate and -isonicotinate were synthesized from the corresponding pyridine esters in 58 and 65% yield. Less stable ethyl 4-iodonicotinate also formed under the same conditions and was directly converted to ethyl 4-(pyrazol-1-yl)nicotinate in a two-step 38% yield. All three ethyl iodopyridinecarboxylates were involved in a one-pot palladium-catalyzed cross-coupling reaction/cyclization using 2-aminopyridine to afford new dipyrido[1,2-a:3',2'-d]pyrimidin-11-one, dipyrido[1,2-a:4',3'-d]pyrimidin-11-one, and dipyrido[1,2-a:3',4'-d]pyrimidin-5-one in yields ranging from 50 to 62%. A similar cross-coupling/cyclization sequence was applied to methyl 2-chloronicotinate using 2-aminopyridine, 2-amino-5-methylpyridine, and 1-aminoisoquinoline to give the corresponding tricyclic or tetracyclic compounds in 43-79% yield. Dipyrido[1,2-a:4',3'-d]pyrimidin-11-one and dipyrido[1,2-a:3',4'-d]pyrimidin-5-one showed a good bactericidal activity against Pseudomonas aeroginosa . Dipyrido[1,2-a:2',3'-d]pyrimidin-5-one and pyrido[2',3':4,5]pyrimidino[2,1-a]isoquinolin-8-one showed a fungicidal activity against Fusarium and dipyrido[1,2-a:4',3'-d]pyrimidin-11-one against Candida albicans . Ethyl 4-(pyrazol-1-yl)nicotinate and dipyrido[1,2-a:2',3'-d]pyrimidin-5-one have promising cytotoxic activities, the former toward a liver carcinoma cell line (HEPG2) and the latter toward a human breast carcinoma cell line (MCF7).

Direct metallation of thienopyrimidines using a mixed lithium-cadmium base and antitumor activity of functionalized derivatives.

A series of thieno[2,3-d]- and thieno[3,2-d]pyrimidines have been easily synthesized using as key step a deproto-cadmiation-trapping sequence. Some of the compounds thus synthesized were screened for anticancer (cytotoxic) activities, and (S)-2-(6-iodo-2-phenylthieno[2,3-d]pyrimidin-4-ylamino)-3-phenylpropanoic acid proved to have a significant activity towards liver, human breast and cervix carcinoma cell lines.