6-Amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides: Synthesis, Biological Activity, Quantum Chemical Studies and In Silico Docking Studies.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N'-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or via a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalondianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichloro- phenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was confirmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computational scheme. The results revealed that the rate-limiting step is a cyclization process leading to the closure of the 1,4-dihydropyridine ring, with an activation barrier of 28.8 kcal/mol. Some of the dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were calculated and molecular docking studies were performed to identify potential protein targets.

Synthesis of ß-Carbolines with Electrocyclic Cyclization of 3-Nitrovinylindoles.

The ß-carboline motif is common in drug discovery and among numerous biologically active natural products. However, its synthetic preparation relies on multistep sequences and heavily depends on the type of substitution required in the core of the desired ß-carboline target. Herein, we demonstrate that this structural motif can be accessed with the microwave-assisted electrocyclic cyclization of heterotrienic aci (alkylideneazinic acid) forms of 3-nitrovinylindoles. The reaction can start with 3-nitrovinylindoles themselves under two sets of conditions. The first one involves microwave irradiation of butanolic solutions of 3-nitrovinylindoles, whereas the second one consists of prior Boc protection of indolic nitrogen, where the protecting group cleanly comes off during the course of the reaction. Alternatively, the reaction can start with 3-nitrovinylindoles prepared in situ using various processes. Finally, the reaction may utilize indoles with ß-nitrostyrenes, likely involving the intermediacy of spirocyclic oxazolines, which rearrange to similar heterotrienic systems undergoing cyclization to ß-carbolines. As part of this study, several natural products, namely, alkaloids norharmane, harmane, and eudistomin N, were synthesized.

New 6'-Amino-5'-cyano-2-oxo-1,2-dihydro-1'H-spiro[indole-3,4'-pyridine]-3'-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity.

The purpose of this work was to prepare new isatin- and monothiomalondiamide-based indole derivatives, as well as to study the properties of the new compounds. The four-component reaction of 5-R-isatins (R = H, CH3), malononitrile, monothiomalonamide (3-amino-3-thioxo- propanamide) and triethylamine in hot EtOH yields a mixture of isomeric triethylammonium 6'-amino-3'-(aminocarbonyl)-5'-cyano-2-oxo-1,2-dihydro-1'H- and 6'-amino-3'-(aminocarbonyl)- 5'-cyano-2-oxo-1,2-dihydro-3'H-spiro[indole-3,4'-pyridine]-2'-thiolates. The reactivity and structure of the products was studied. We found that oxidation of spiro[indole-3,4'-pyridine]-2'-thiolates with DMSO-HCl system produced only acidification products, diastereomeric 6'-amino-5'-cyano-5-methyl-2-oxo-2'-thioxo-1,2,2',3'-tetrahydro-1'H-spiro-[indole-3,4'-pyridine]- 3'-carboxamides, instead of the expected isothiazolopyridines. The alkylation of the prepared spiro[indole-3,4'-pyridine]-2'-thiolates upon treatment with N-aryl α-chloroacetamides and α-bromoacetophenones proceeds in a regioselective way at the sulfur atom. In the case of α-bromoacetophenones, ring-chain tautomerism was observed for the S-alkylation products. According to NMR data, the compounds consist of a mixture of stereoisomers of 2'-amino-6'-[(2-aryl-2-oxoethyl)thio]-3'-cyano-2-oxo-1'H-spiro[indoline-3,4'-pyridine]-5'-carboxamides and 5'-amino-3'-aryl-6'-cyano-3'-hydroxy-2-oxo-2',3'-dihydrospiro[indoline-3,7'-thiazolo[3,2-a]pyridine]-8'-carboxamides in various ratios. The structure of the synthesized compounds was confirmed by IR spectroscopy, HRMS, 1H and 13C DEPTQ NMR studies and the results of 2D NMR experiments (1H-13C HSQC, 1H-13C HMBC). Molecular docking studies were performed to investigate suitable binding modes of some new compounds with respect to the transcriptional regulator protein PqsR of Pseudomonas aeruginosa. The docking studies revealed that the compounds have affinity for the bacterial regulator protein PqsR of Pseudomonas aeruginosa with a binding energy in the range of -5.8 to -8.2 kcal/mol. In addition, one of the new compounds, 2'-amino-3'-cyano-5-methyl-2-oxo-6'-{[2-oxo-2-(p-tolylamino)ethyl]thio}-1'H-spiro-[indoline-3,4'-pyridine]-5'-carboxamide, showed in vitro moderate antibacterial effect against Pseudomonas aeruginosa and good antioxidant properties in a test with 1,1-diphenyl-2-picrylhydrazyl radical. Finally, three of the new compounds were recognized as moderately active herbicide safeners with respect to herbicide 2,4-D in the laboratory experiments on sunflower seedlings.

Alkyl 4-Aryl-6-amino-7- phenyl-3-(phenylimino)-4,7-dihydro- 3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylates: Synthesis and Agrochemical Studies.

The reaction between dithiomalondianilide (N,N'-diphenyldithiomalondiamide) and alkyl 3-aryl-2-cyanoacrylates in the presence of morpholine in the air atmosphere leads to the formation of alkyl 6-amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]- pyridine-5-carboxylates in 37-72% yields. The same compounds were prepared in 23-65% yields by ternary condensation of aromatic aldehydes, ethyl(methyl) cyanoacetate and dithiomalondianilide. The reaction mechanism is discussed. The structure of ethyl 6-amino-4-(4-methoxyphenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylate was confirmed by X-ray crystallography. Two of the prepared compounds showed a moderate growth-stimulating effect on sunflower seedlings. Three of the new compounds were recognized as strong herbicide safeners with respect to herbicide 2,4-D in the laboratory and field experiments on sunflower.

The Reactions of N,N'-Diphenyldithiomalondiamide with Arylmethylidene Meldrum's Acids.

The Michael addition reaction between dithiomalondianilide (N,N'-diphenyldithiomalondiamide) and arylmethylidene Meldrum's acids, accompanied by subsequent heterocyclization, was investigated along with factors affecting the mixture composition of the obtained products. The plausible mechanism includes the formation of stable Michael adducts which, under the studied conditions, undergo further transformations to yield corresponding N-methylmorpholinium 4-aryl-6-oxo-3-(N-phenylthio-carbamoyl)-1,4,5,6-tetrahydropyridin-2-thiolates and their oxidation derivatives, 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones. The structure of one such product, N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate, was confirmed via X-ray crystallography.

Benzimidazoles and benzoxazoles via the nucleophilic addition of anilines to nitroalkanes.

PPA-induced umpolung triggers efficient nucleophilic addition of unactivated anilines to nitroalkanes to produce N-hydroxyimidamides. The latter undergo sequential acid-promoted cyclocondensation with ortho-OH or ortho-NHR moieties to afford benzoxazoles and benzimidazoles, respectively.

Highly efficient modular metal-free synthesis of 3-substituted 2-quinolones.

A modular approach to 3-substituted 2-quinolones via a cascade annulation reaction between 4-nitroketones and hydrazines has been developed.

Nitrovinylindoles as Heterotrienes: Electrocyclic Cyclization En Route to ß-Carbolines: Total Synthesis of Alkaloids Norharmane, Harmane, and Eudistomin N.

Unusual cascade transformation was developed involving microwave assisted electrocyclic cyclization of aci (alkylideneazinic acid) forms of nitrovinylindoles acting as heterotrienes. Subsequent one-pot reduction allowed for efficient access to ß-carbolines, including several natural products, alkaloids norharmane, harmane and eudistomin N.

2-Amino-4,5-dihydrothiophene-3-carbonitriles: A New Synthesis, Quantum Chemical Studies, and Mannich-Type Reactions Leading to New Hexahydrothieno[2,3-d]pyrimidines.

trans-2-Amino-4-aryl-5-benzoyl-4,5-dihydrothiophene-3-carbonitriles were prepared either by the reaction of 3-aryl-2-cyanothioacrylamides with α-thiocyanatoacetophenone or by the Michael-type addition of cyanothioacetamide to α-bromochalcones followed by intramolecular cyclization. The mechanism of the first reaction was studied using high-level quantum chemical calculations. Density functional theory (DFT) studies were carried out to determine the mechanism of the first reaction. A new approach toward the construction of the thieno[2,3-d]pyrimidine core system was demonstrated by the reaction of the prepared dihydrothiophenes with HCHO and RNH2 under noncatalyzed Mannich conditions.

Activity of 2-aryl-2-(3-indolyl)acetohydroxamates against drug-resistant cancer cells.

Many types of tumor, including glioma, melanoma, non-small cell lung, esophageal, and head and neck cancer, among others, are intrinsically resistant to apoptosis induction and poorly responsive to current therapies with proapoptotic agents. In addition, tumors often develop multidrug resistance based on the cellular efflux of chemotherapeutic agents. Thus, novel anticancer agents capable of overcoming these intrinsic or developed tumor resistance mechanisms are urgently needed. We describe a series of 2-aryl-2-(3-indolyl)acetohydroxamic acids that are active against apoptosis- and multidrug-resistant cancer cells as well as glioblastoma neurosphere stemlike cell cultures derived from patients. Thus, the described compounds serve as a novel chemical scaffold for the development of potentially highly effective clinical cancer drugs.

Metal-free transannulation reaction of indoles with nitrostyrenes: a simple practical synthesis of 3-substituted 2-quinolones.

3-Substituted 2-quinolones are obtained via a novel, metal-free transannulation reaction of 2-substituted indoles with 2-nitroalkenes in polyphosphoric acid. The reaction can be used in conjunction with the Fisher indole synthesis offering a practical three-component heteroannulation methodology to produce 2-quinolones from arylhydrazines, 2-nitroalkenes and acetophenone.