Investigation of cholinesterase and α-glucosidase enzyme activities, and molecular docking and dft studies for 1,2-disubstituted cyclopentane derivatives with phenyl and benzyl units.

Six known products (4-9) were prepared from reaction of adipoyl chloride with 1,2,3-trimethoxybenzene according to the literature. From (2,3,4-trimethoxyphenyl)(2-(2,3,4-trimethoxyphenyl)cyclopent-1-en-1-yl)methanone (4) of them, four new 1,2-disubstituted cyclopentane derivatives (10-13) with phenyl and benzyl units were synthesized by reactions such as hydrazonation, catalytic hydrogenation and bromination. The obtained compounds 4-13 were examined for their in vitro inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and α-glucosidase enzymes. All compounds 4-13 showed inhibition at nanomolar level with Ki values in the range of 45.53 ± 7.35-631.96 ± 18.88 nM for AChE, 84.30 ± 9.92-622.10 ± 35.14 nM for BChE, and 25.47 ± 4.46-48.87 ± 7.33 for α-Glu. In silico molecular docking studies of the potent compounds were performed in the active sites of AChE (PDB: 1E66), BChE (PDB: 1P0I), and α-glucosidase (PDB: 5ZCC) to compare the effect of bromine atom on the inhibition mechanism. The optimized molecular structures, HOMO-LUMO energies and molecular electrostatic potential maps for the compounds were calculated by using density functional theory with B3LYP/6-31 + G(d,p).

Novel Quinoline-Based Thiosemicarbazide Derivatives: Synthesis, DFT Calculations, and Investigation of Antitubercular, Antibacterial, and Antifungal Activities.

The discovery of new antimicrobial agents as a means of treating drug-resistant microbial pathogens is of utmost significance to overcome their immense risk to human well-being. The current investigation involves the development, synthesis, and assessment of the antimicrobial efficacy of novel quinoline derivatives incorporating a thiosemicarbazide functionality. To design the target compounds (QST1-QST14), we applied the molecular hybridization approach to link various thiosemicarbazides to the quinoline core with a sulfonyl group. Upon the synthesis and completion of structural characterization via spectroscopic techniques (1H NMR, 13C NMR, 15N NMR, IR, and HRMS), the title molecules were extensively evaluated for their potential antitubercular, antibacterial, and antifungal activities. N-(3-Chlorophenyl)-2-(quinolin-8-ylsulfonyl)hydrazine-1-carbothioamide (QST4), the most effective compound against Mycobacterium tuberculosis H37Rv, was also tested on isoniazid-resistant clinical isolates with katG and inhA promoter mutations. Based on molecular docking studies, QST4 was also likely to demonstrate its antimycobacterial activity through inhibition of the InhA enzyme. Furthermore, three derivatives (QST3, QST4, and QST10) with preferable antimicrobial and drug-like profiles were also shown to be nontoxic against human embryonic kidney (HEK) cells. All compounds were optimized by the density functional theory method using B3LYP with the 6-31+G(d,p) basis set. Structural analysis, natural bond orbital calculations of donor-acceptor interactions, molecular electrostatic potential analysis, and frontier molecular orbital analysis were carried out. Quantum chemical descriptors and charges on the atoms were determined to compare the strengths of the intramolecular hydrogen bonds formed and their stabilities. We determined that the sulfur atom forms a stronger intramolecular hydrogen bond than the nitrogen, oxygen, and fluorine atoms in these sulfonyl thiosemicarbazide derivatives.

AlCl3-Catalyzed Cascade Reactions of 1,2,3-Trimethoxybenzene and Adipoyl Chloride: Spectroscopic Investigations and Density Functional Theory Studies.

The reaction of 1,2,3-trimethoxybenzene with adipoyl chloride in the presence of AlCl3 gave two isomeric cyclopentene derivatives, 1,6-bis(2,3,4-trimethoxyphenyl)hexane-1,6-dione, and two demethylation products of aryl methyl ethers. The cyclopentene derivatives including unconjugated or conjugated enones are products formed in a cascade reaction resulting from first the Friedel-Crafts acylation reaction and then aldol condensation. All compounds were optimized by density functional theory calculated using two functional levels, B3LYP and M06-2X, with the 6-311+G(d,p) basis set. The structural properties were established, natural bond orbital analysis of donor-acceptor interactions was carried out, and charges on the atoms and quantum chemical reactivity identifiers were determined to compare the strength of the intramolecular hydrogen bonds formed and their stabilities. To compare the experimental 1H and 13C NMR chemical shifts with the calculated values, NMR chemical shift calculations were carried out using the gauge-invariant atomic orbital method.

One-pot synthesis of oxazolidinones and five-membered cyclic carbonates from epoxides and chlorosulfonyl isocyanate: theoretical evidence for an asynchronous concerted pathway.

The one-pot reaction of chlorosulfonyl isocyanate (CSI) with epoxides having phenyl, benzyl and fused cyclic alkyl groups in different solvents under mild reaction conditions without additives and catalysts was studied. Oxazolidinones and five-membered cyclic carbonates were obtained in ratios close to 1:1 in the cyclization reactions. The best yields of these compounds were obtained in dichloromethane (DCM). Together with 16 known compounds, two novel oxazolidinone derivatives and two novel cyclic carbonates were synthesized with an efficient and straightforward method. Compared to the existing methods, the synthetic approach presented here provides the following distinct advantageous: being a one-pot reaction with metal-free reagent, having shorter reaction times, good yields and a very simple purification method. Moreover, using the density functional theory (DFT) method at the M06-2X/6-31+G(d,p) level of theory the mechanism of the cycloaddition reactions has been elucidated. The further investigation of the potential energy surfaces associated with two possible channels leading to oxazolidinones and five-membered cyclic carbonates disclosed that the cycloaddition reaction proceeds via an asynchronous concerted mechanism in gas phase and in DCM.

Antidiabetic potential: In vitro inhibition effects of bromophenol and diarylmethanones derivatives on metabolic enzymes.

Aldose reductase converts glucose to sorbitol in the polyol pathway. It is an important enzyme to prevent diabetic complications. In this study, we studied the inhibitory effects of bromophenol derivatives on aldose reductase (AR), α-glucosidase, and α-amylase enzymes. In the bromophenols series, compound 1f showed the maximum inhibition effect against AR with a Ki value of 0.05 ± 0.01 µM, while compound 1d showed the lowest inhibition effect against AR with a Ki value of 1.13 ± 0.99 µM. In addition, α-amylase from porcine pancreas and α-glucosidase from Saccharomyces cerevisiae were used as enzymes. In this study, all compounds were tested for the inhibition of the α-glucosidase enzyme and demonstrated efficient inhibition profiles with Ki values in the range of 43.62 ± 5.28 to 144.37 ± 16.37 nM against α-glucosidase. Additionally, these compounds were tested against the α-amylase enzyme, which determined an effective inhibition profile with IC50 values in the range of 9.63-91.47 nM. These compounds can be selective inhibitors of AR, α-glucosidase, and α-amylase enzymes as antidiabetic agents.

The effects of some bromophenols on human carbonic anhydrase isoenzymes.

Carbonic anhydrases (CAs, EC 4.2.1.1), which are involved in a variety of physiological and pathological processes, are ubiquitous metalloenzymes mainly catalyzing the reversible hydration of carbon dioxide (CO2) to bicarbonate ([Formula: see text]) and proton (H(+)). In this study, a dozen of bromophenol derivatives (1-12) were evaluated as metalloenzyme CA (EC 4.2.1.1) inhibitors against the human carbonic anhydrase isoenzymes I and II (hCA I and II). Cytosolic hCA I and II isoenzymes were effectively inhibited by bromophenol derivatives (1-12) with Kis in the low nanomolar range of 1.85 ± 0.58 to 5.04 ± 1.46 nM against hCA I and in the range of 2.01 ± 0.52 to 2.94 ± 1.31 nM against hCA II, respectively.

Synthesis of 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene Derivatives and Evaluations of Their Carbonic Anhydrase Isoenzymes Inhibitory Effects.

Rearrangement of 1,6-bis(3,4-dimethoxyphenyl)hexane-1,6-dione (8) gave two isomeric products having cyclopentene moiety. Starting from the major product (3,4-dimethoxyphenyl)[2-(3,4-dimethoxyphenyl)cyclopent-1-en-1-yl]methanone (11), eight new compounds (16-23) were obtained by the reactions such as reduction (by catalytic hydrogenation and NaBH4 ), nitration, 1,4-addition, bromination, and esterification reactions. Carbonic anhydrases (CA, E.C.4.2.1.1) are ubiquitous metalloenzymes present in almost all living organism that catalyze a simple reaction, the conversion of carbon dioxide (CO2 ) and water (H2 O) to bicarbonate ion (HCO3 (-) ) and a proton (H(+) ). CA isoenzymes I and II (hCA I and II) inhibition effects of synthesized eleven new and four known compounds (8-13 and 15-23) were investigated. Inhibition studies of the hCA I and II with 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene derivatives revealed that they possess effective inhibitory potency. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene derivatives with Ki s in the range of 313.16-1537.00 nm against hCA I and in the range of 228.31-1927.31 nm against hCA II, respectively.

Antioxidant and acetylcholinesterase inhibition properties of novel bromophenol derivatives.

In this study, series of novel bromophenol derivatives were synthesized and investigated for their antioxidant and AChE inhibition properties. Novel brominated diarylmethanones were obtained from the acylation reactions of benzoic acids with substituted benzenes. One of the bromodiarylmethanone was synthesized from the bromination of diarylmethanone with molecular bromine. All diarylmethanones were converted into their bromophenol derivatives with BBr3. The antioxidant activities of all synthesized compounds were elucidated by using various bioanalytical assays. Radical scavenging activities of compounds 10-24 were evaluated by means of DPPH and ABTS(+) scavenging activities. In addition, reducing ability of 10-24 were determined by Fe(3+), Cu(2+), and [Fe(3+)-(TPTZ)2](3) reducing activities. α-Tocopherol, trolox, BHA, and BHT were used as positive antioxidant and radical scavenger molecules. On the other hand, IC50 values were calculated for DPPH, ABTS(+) scavenging, and AChE inhibition effects of novel compounds. The results obtained from the current studies clearly show that novel bromophenol derivatives 20-24 have considerable antioxidant, antiradical, and AChE inhibition effects.

Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxybromophenol derivatives incorporating cyclopropane moieties.

Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which after bromination with Br2 gave two isomeric monobromides (11 and 15), four isomeric dibromides (12, 13, 16, and 17), and two isomeric tribromides (14 and 18). The carboxylic acids 7, 8, and 19-26 were thereafter obtained by hydrolysis of the synthesized esters. All these bromophenol derivatives were tested against human (h) CA isoenzymes I and II (cytosolic, ubiquitous isoforms) and hCA IX and XII (transmembrane, tumor-associated enzymes). All tested bromophenols exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 0.54-59 nM against hCA I and in the range of 0.97-12.14 nM against hCA II, whereas they were low micromolar inhibitors against hCA IX and XII. The best hCA I inhibition was observed in new bromophenol derivative 20 (Ki = 0.54 nM). On the other hand, new bromophenol derivative 12 showed a powerful inhibition effect against hCA II (Ki = 0.97 nM).

Synthesis and carbonic anhydrase isoenzymes inhibitory effects of brominated diphenylmethanone and its derivatives.

Known and novel derivatives including CO, Br, and OH (benzylic and phenolic), and the corresponding benzylic alcohols of (3,4-dimethoxyphenyl)(2,3,4-dimethoxyphenyl)methanone were synthesized, and their inhibitory effects on the carbonic anhydrase (CA) isoenzymes I and II were investigated. CAs are the metalloenzymes catalyzing the reversible hydration of carbon dioxide (CO2 ) to bicarbonate (HCO3 (-) ). The inhibitory effects of diphenylmethanone derivatives 5-18 were tested on human CA (hCA, EC 4.2.1.1) isoenzymes (hCA I and hCA II) and they inhibited both isoenzymes at micromolar levels. Compounds 5 and 10 were found to be the best inhibitors against both CA isoenzymes. According to our data, compound 10 was the best inhibitor for isoenzyme hCA I (IC50 = 3.48 µM, Ki = 2.19 µM) whereas compound 5 was found to be the best inhibitor for isoenzyme hCA II (IC50 = 1.33 µM, Ki = 2.09 µM). Probably, stable conformations of 5 and 10 are more convenient for interaction with CA isoenzymes than those of the other compounds.

Synthesis and carbonic anhydrase isoenzymes I and II inhibitory effects of novel benzylamine derivatives.

Synthesis and carbonic anhydrase inhibitory properties of novel diarylmethylamines 22-25 and sulfonamide derivatives 26-28 were investigated. Acylation of methoxy-substituted benzenes with benzene carboxylic acids, reduction of ketones with NaBH4, conversion of alcohols to azides, Pd-C catalyzed hydrogenation of azides afforded title compounds 22-25. Compounds 22, 24 and 25 were converted to sulfonamide derivatives 26-28 with MeSO2Cl. The inhibitory effects of novel benzylamine derivatives 22-28 were tested on human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes hCA I and II. The results demonstrated that compound 28 was found to be the best inhibitor against both hCA I (Ki: 3.68 µM) and hCA II (Ki: 9.23 µM).

(3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors.

In this study, we have synthesised (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and a series of its derivatives (5, 13-16) and tested the ability of these compounds to inhibit two metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I and hCA II. The synthesised compounds showed inhibitory effect on hCA I and hCA II isozymes. The results showed that synthesised compounds (5, 13-16) demonstrated the best inhibition activity against hCA I (IC(50): 3.22-54.28 µM) and hCA II (IC(50): 18.52-142.01 µM). The compound 14 showed the highest inhibiton effect against hCA I (IC(50): 3.22 µM; K(i): 1.19 ± 1.4 µM). On the other hand, the compound 13 showed the highest inhibiton effect against hCA II (IC(50): 18.52 µM; K(i): 3.25 ± 1.13 µM).

Synthesis and antioxidant properties of (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives.

(3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone (5) and its two derivatives with bromine were synthesized from reactions such as bromination and demethylation of (3,4-dimethoxyphenyl)(2,3,4-trimethoxyphenyl)methanone (6). The Wolf-Kishner reduction product (9) of 6 and its three derivatives with bromine were obtained. 4-(3,4-Dihydroxybenzyl)benzene-1,2,3-triol and its dibromide derivative (16) were also synthesized from 9 and the corresponding dibromide derivative. The in vitro antioxidant activities of nine new compounds synthesized in these reactions were determined by analyzing the radical scavenging activities of bromophenols for 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picryl-hydrazyl (DPPH), N,N-dimethyl-p-phenylenediamine (DMPD), and the superoxide anion radical (O(2)(·-)) and examining the total reducing power through Fe(3+)-Fe(2+) transformation, FRAP and CUPRAC assays and the ferrous ions (Fe(2+)) chelating activities. Moreover, the results of these activities were compared to those of standard antioxidant compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol, and trolox. The results showed that the synthesized bromophenols had effective antioxidant power. The phenol 5 with two phenolic rings and five phenolic hydroxyl groups was the most potent antioxidant and radical scavenger. In conclusion, the new compounds are promising molecules to be used owing to their potential antioxidant properties.

(1RS,2RS,3SR,5RS,7RS)-2,5-Dichloro-8-oxabicyclo-[5.1.0]octan-3-ol.

In the title compound, C(7)H(10)Cl(2)O(2), the seven-membered ring displays a chair conformation. In the crystal, the hy-droxy H atom is equally disordered over two orientations, and links with an adjacent mol-ecule via an O-H⋯O hydrogen bond in both cases. Weak inter-molecular C-H⋯O hydrogen bonding is also a feature of the crystal structure.