Anionic photochemical rearrangement of 3-hydroxypyran-4-ones bearing oxazol-2-one fragment.

The photochemical behavior of in situ generated anions of 3-hydroxypyran-4-ones containing an oxazol-2-one moiety was studied. For the first time, it was demonstrated that blue LED light irradiation (450 nm) of substituted 3-hydroxypyran-4-ones in the presence of a base leads regiospecifically to the formation of isomeric 3-hydroxypyran-2-ones. Transformation of the starting 3-hydroxypyran-4-ones into the corresponding anions is necessary for the presented photoprocess. Based on the considered visible light induced rearrangement, a general method for the synthesis of 3-hydroxypyran-2-ones with an oxazol-2-one moiety was elaborated. The structure of one of the synthesized compounds was confirmed by X-ray diffraction.

1,1'-Carbonyldiimidazole-mediated transformation of allomaltol containing hydrazides into substituted 3-acetyltetronic acids.

For the first time, the reaction of allomaltol containing hydrazides with 1,1'-carbonyldiimidazole (CDI) was studied. It was shown that under the considered conditions, 3-hydroxy-4-pyranone derivatives were transformed into 3-acetyltetronic acids bearing a pyrrolidin-2-one moiety. We have found that the key intermediates of the investigated process are substituted 6-oxa-1-azaspiro[4.5]dec-7-ene-2,9-diones. The structures of one final product and one intermediate were confirmed by X-ray analysis. The disclosed reaction was tested using a wide range of substituted allomaltols with various carboxamide units. It was demonstrated that in the case of hetaryl containing hydrazides and hydroxamic acids, the direction of the process is completely changed and cyclization into substituted pyrano[3,2-b]pyrans occurs.

Synthesis of substituted 8H-benzo[h]pyrano[2,3-f]quinazolin-8-ones via photochemical 6π-electrocyclization of pyrimidines containing an allomaltol fragment.

For the first time, we elaborated a method for the synthesis of pyrimidines containing an allomaltol unit. The suggested approach is based on the reaction of 2-(1-(dimethylamino)-3-oxo-3-arylprop-1-en-2-yl)-3-hydroxy-6-methyl-4H-pyran-4-ones with cyanamide. The photochemical behavior of the obtained pyrimidines was investigated. It was shown that for the hydroxy derivatives the main pathway of phototransformation is a 6π-electrocyclization of the 1,3,5-hexatriene system and subsequent [1,9]-H sigmatropic shift leading to dihydrobenzo[h]pyrano[2,3-f]quinazolines. At the same time, for methylated analogues the photoreaction proceeds in two directions resulting in the formation of a mixture of the corresponding dihydrobenzo[h]pyrano[2,3-f]quinazolines and polyaromatic products. The obtained dihydro derivatives are stable compounds and do not undergo aromatization upon further UV irradiation. The structures of two of the dihydrobenzo[h]pyrano[2,3-f]quinazolines were confirmed by X-ray diffraction analysis. Based on the performed studies, a two-stage telescopic method for the synthesis of polyaromatic benzo[h]pyrano[2,3-f]quinazolines including the initial photocyclization of the starting pyrimidines and the final dehydration was proposed.

Substituted furan sulfonamides as carbonic anhydrase inhibitors: Synthesis, biological and in silico studies.

Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several of biological processes, such as respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show wide diversity in tissue distribution and in their subcellular localization. Fifteen novel furyl sulfonamides were designed, synthesized and evaluated against four human isoforms: hCA I, hCA II, hCA IV and hCA IX. Compounds appeared to be very active mostly against hCAI (8) and hCA IV (11) isoforms being more potent than reference drug acetazolamide (AAZ). It should be mentioned that four compounds were more active than AAZ against hCA IX isoform, with compound 13d to be selective against hCA I (SI 70), hCA II (SI 13.5) and hCA IV (SI 20). Furthermore, docking was performed for some of these compounds on all isoforms I order to understand the possible interactions with the active site. The most active compounds showed good bioavailability and drug likeness scores.

Photochemical synthesis and ring-chain-ring tautomerism of benzo[4,5]imidazo[1,2-a]cyclopenta[e]pyridines.

UV-mediated approach for the preparation of benzo[4,5]imidazo[1,2-a]cyclopenta[e]pyridine derivatives from allomaltols containing a benzimidazole fragment was developed. The suggested method includes ESIPT-induced contraction of a 3-hydroxypyran-4-one core and further intramolecular trapping of unstable α-hydroxy-1,2-diketone. The distinctive feature of the obtained photoproducts is ring-chain-ring tautomerism in solution. Based on X-ray analysis, the obtained photoproducts in the solid state exist in one isomeric form. Various types of derivatization of the synthesized compounds allow both forms of tautomers to be trapped.

Synthesis, Biological and In Silico Studies of Griseofulvin and Usnic Acid Sulfonamide Derivatives as Fungal, Bacterial and Human Carbonic Anhydrase Inhibitors.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of griseofulvin and usnic acid sulfonamides were synthesized and tested as possible CA inhibitors. Since ß- and γ- classes are expressed in microorganisms in addition to the α- class, showing substantial structural differences to the human isoforms they are also interesting as new antiinfective targets with a different mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Griseofulvin and usnic acid sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX as well as ß- and γ-CAs from different bacterial and fungal strains, was evaluated by a stopped-flow CO2 hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the three γ-CAs and Malassezia globosa (MgCA) enzyme. Six compounds (1b-1d, 1h, 1i and 1j) were more potent than AAZ against hCA I while five (1d, 1h, 1i, 1j and 4a) showed better activity than AAZ against the hCA II isoform. Moreover, all compounds appeared to be very potent against MgCA with a Ki lower than that of the reference drug. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of human CAs.

A study of the photochemical behavior of terarylenes containing allomaltol and pyrazole fragments.

The photochemical properties behavior of 3-hydroxy-4-pyranone containing terarylenes with a pyrazole bridge fragment were studied. It was shown that UV-induced 6π-electrocyclization of the 1,3,5-hexatriene system was not observed for the considered objects molecules. At the same time, the phototransformation of such systems proceeds exclusively in the direction of the contraction of the pyranone ring leading to unstable α-hydroxydiketones. For the first time the possibility of isolation of the resulting α-hydroxydiketones in pure form was demonstrated. Wherein, it was shown that relatively low stable α-hydroxydiketones can be trapped by reaction with 1,2-phenylenediamine. The general method for the preparation of the corresponding quinoxalines on the basis of the aforementioned condensation was implemented. It was demonstrated that the studied photoreaction does not depend on the type of pyrazole bridge. The structures of three of synthesized products were established by X-ray diffraction.

Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. On the other hand, in microorganisms, the ß- and γ- classes are expressed in addition to the α- class, showing substantial structural differences to the human isoforms. In this scenario, not only human but also bacterial CAs are of particular interest as new antibacterial agents with an alternative mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Pyrazolo[4,3-c]pyridine sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX and XII, and ß- and γ-CAs from three different bacterial strains, was evaluated by a stopped-flow CO2 hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the 3ß- and 3γ-CAs. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX. Four compounds (1f, 1g, 1h and 1k) were more potent than AAZ against hCA I. Furthermore, compound 1f also showed better activity than AAZ against the hCA II isoform. Moreover, ten compounds out of eleven appeared to be very potent against the γ-CA from E.coli, with a Ki much lower than that of the reference drug. Most of the compounds showed better activity than AAZ against hCA I as well as the γ-CA from E.coli and the ß-CA from Burkholderia pseudomallei (BpsCAß). Compounds 1f and 1k showed a good selectivity index against hCA I and hCA XII, while 1b was selective against all 3ß-CA isoforms from E.coli, BpsCA, and VhCA and all 3γ-CA isoforms from E.coli, BpsCA and PgiCA.

Photoinduced assembly of the 3,4,4a,7a-tetrahydro-1H-cyclopenta[b]pyridine-2,7-dione core on the basis of allomaltol derivatives.

A novel photochemical method for the construction of previously unknown substituted 4a,7a-dihydroxy-5-methyl-3,4,4a,7a-tetrahydro-1H-cyclopenta[b]pyridine-2,7-diones based on readily available allomaltol derivatives containing an amide group was established. The proposed approach includes the photoinduced contraction of an allomaltol ring and the subsequent intramolecular cyclization of an unstable α-hydroxy-1,2-diketone intermediate. For the first time we have shown the use of a side chain amide function as a trapping element for the final cyclization of photogenerated α-hydroxy-1,2-diketones. The structures of two synthesized photoproducts were determined by X-ray diffraction.

Photoinduced 6π-Electrocyclization of a 1,3,5-Hexatriene System Containing an Allomaltol Fragment.

For the first time, the possibility of photocyclization of the 1,3,5-hexatriene system containing a fragment of allomaltol was demonstrated. A preparative method for the synthesis of previously unknown benzo[5,6]chromeno[8,7-d]oxazole-2,7(3H)-diones was developed based on the investigated photoreaction. A distinctive feature of this approach is the modification of the starting terarylenes aimed at blocking the competitive process leading to side reactions of the pyranone fragment. It was shown that the proposed photocyclization of substituted oxazol-2-ones can be used for the photogeneration of biologically active alcohols and various acids. The structure of one of the cyclization products was determined by X-ray diffraction.

Construction of Spiro-γ-butyrolactone Core via Cascade Photochemical Reaction of 3-Hydroxypyran-4-one Derivatives.

We elaborate a novel one-step photochemical method for the synthesis of spiro-γ-butyrolactone derivatives from 3-hydroxypyran-4-ones. The suggested approach is based on a cascade process including initial photoinduced contraction of 4-pyranone ring followed by intramolecular cyclization leading to the final spiro system. A distinctive feature of the proposed method is intramolecular trapping of unstable α-hydroxydiketone intermediate formed in situ as a result of a photochemical reaction. The structures of two synthesized 1-oxaspiro[4.4]non-8-ene-2,6,7-triones were determined by X-ray diffraction.

2-Nitroallyl carbonate-based green bifunctional reagents for catalytic asymmetric annulation reactions.

2-Nitroallylic carbonates, a new class of "green" 1,3-bielectrophilic reagents for organic synthesis and catalysis, have been prepared. The bifunctional tertiary amine-catalyzed asymmetric [3 + 3] annulations of cyclic enols with these reagents occur much faster than corresponding reactions with 2-nitroallylic esters and produce no acidic by-products poisoning the catalyst. Furthermore, 2-nitroallylic carbonates enable highly enantioselective one-pot synthesis of a variety of fused dihydropyrane derivatives from available precursors bearing pharmacophoric fragments.

Synthesis of substituted naphtho[1,2-b]benzofuran-7(8H)-ones via photoinduced rearrangement of 4H-chromen-4-one derivatives.

A simple and efficient method was developed for the synthesis of substituted naphtho[1,2-b]benzofuran-7(8H)-ones based on the photorearrangement reaction of 4H-chromen-4-one derivatives. The studied reaction includes the photocyclization of the hexatriene system, [1,9]-H-sigmatropic rearrangement and heterocyclic ring opening. The starting terarylenes were prepared via a new three-component tandem condensation of 3-(dimethylamino)-1-(2-hydroxyaryl)prop-2-en-1-ones, arylglyoxals and cyclic 1,3-diketones.

One-pot synthesis of substituted pyrrolo[3,4-b]pyridine-4,5-diones based on the reaction of N-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-arylethyl)acetamide with amines.

The condensation of primary amines with N-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-arylethyl)acetamides was explored. Thus, a previously unknown recyclization of the starting material was observed in acidic ethanol in the presence of an amine, which provided the corresponding dihydropyrrolone derivative as the major reaction product. Based on this transformation, a practical and convenient one-pot synthetic method for substituted pyrrolo[3,4-b]pyridin-5-ones could be devised.

Benzimidazolyl-pyrazolo[3,4-b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest.

1,3-Substituted pyrazolo[3,4-b]pyridinones 11-18 were synthesized by a three-component condensation of Meldrum's acid with aryl aldehydes and 1,3-substituted 5-aminopyrazoles. Their biological activity was evaluated using the in vivo phenotypic sea urchin embryo assay and the in vitro cytotoxicity screen against human cancer cell lines. In the sea urchin embryo model, 1-benzimidazolyl-pyrazolo[3,4-b]pyridinones 11 caused inhibition of hatching and spiculogenesis at sub-micromolar concentrations. These compounds also selectively and potently inhibited growth of the MOLT-4 leukemia cell line. Subsequent structure-activity relationship studies determined the benzimidazolyl fragment as an essential pharmacophore for both effects. We applied numerous techniques for target identification. A preliminary QSAR target identification search did not result in tangible leads. Attempts to prepare a relevant photoaffinity probe that retained potency in both assays were not successful. Compounds 11 were further characterized for their activity in a wild-type versus Notch-mutant leukemia cell lines, and in in vitro panels of kinases and matrix metalloproteinases. Using a series of diverse modulators of spiculogenesis as standards, we excluded multiple signaling networks including Notch, Wnt/ß-catenin, receptor tyrosine kinases (VEGF/VEGFR, FGF/FGFR), PI3K, and Raf-MEK-ERK as possible targets of 11. On the other hand, matrix metalloproteinase-9/hatching enzyme was identified as one potential target.

C2-Symmetric Chiral Squaramide, Recyclable Organocatalyst for Asymmetric Michael Reactions.

A very simple and highly efficient C2-symmetric tertiary amine-squaramide organocatalyst for asymmetric Michael reactions has been elaborated. In the presence of only 1 mol % of this catalyst, kojic acid derivatives and ß-dicarbonyl compounds reacted with nitroolefins, affording the corresponding adducts in a nearly quantitative yield with an enantioselectivity up to 99% ee. The kojic acid-derived adducts could be efficiently produced under "green" conditions (in 96% EtOH or pure water). Moreover, due to the very low solubility in organic solvents, the developed nonsupported catalyst could be readily recovered and reused in catalytic reactions up to 7 times. Utmost availability (one-step synthesis without chromatographic purification), high level of stereoinduction, low efficient loading, and recyclability make it attractive for industrial application in the pharmaceutical industry.

Asymmetric Michael addition between kojic acid derivatives and unsaturated ketoesters promoted by C2-symmetric organocatalysts.

An efficient sterically hindered C2-symmetric bifunctional tertiary amine-squaramide organocatalyst for the asymmetric Michael addition/hemiketalization domino reaction of kojic acid derivatives with ß,γ-unsaturated α-ketoesters has been designed. Pharmacology-relevant functionalized 2,3,4,8-tetrahydropyrano[3,2-b]pyran derivatives were produced over the catalyst in as low as 1 mol% with up to 99% yield and 99% ee. The procedure is at least 30-fold scalable and the catalyst is readily reusable in the catalytic reaction via acid-base extraction. Acylation of the products with (S)- or rac-ibuprofen and with undec-10-enoic acid afforded the corresponding chiral esters containing two privileged pharmacophoric motifs.

Synthesis and anti-mitotic activity of 6,7-dihydro-4H-isothiazolo[4,5-b]pyridin-5-ones: In vivo and cell-based studies.

A series of 3,7-diaryl-6,7-dihydroisothiazolo [4,5-b]pyridin-5(4H)-ones 8 and 9 was synthesized by multicomponent condensation of 3-aryl-5-isothiazolecarboxylic acid esters 4a-f with aromatic (or thienyl) aldehydes 7 and Meldrum's acid in an acidic medium. The targeted compounds were evaluated for their antimitotic microtubule destabilizing activity using in vivo phenotypic sea urchin embryo model and in vitro human cancer cell-based assays. Selected dihydroisothiazolopyridinones altered sea urchin egg cleavage in 2-10 nM concentrations together with significant cytotoxicity against cancer cells including chemoresistant cell lines (IC50 in submicromolar - low nanomolar concentration range). Both approaches confirmed antimitotic microtubule destabilizing mechanism of action of the izothiazole derivatives. Structure-activity relationship study determined the importance of p-methoxybenzene A-ring for the antiproliferative effect. The most potent compound 9b containing p-methoxybenzene A-ring and thiophene B-ring caused mitotic arrest and disintegration of cell microtubules.