A Regioselective Synthesis of Novel Functionalized Organochalcogen Compounds by Chalcogenocyclofunctionalization Reactions Based on Chalcogen Halides and Natural Products

The regioselective synthesis of novel functionalized condensed organochalcogen compounds by chalcogenocyclofunctionalization reactions based on chalcogen halides and the natural products thymol and carvacrol has been developed. The reactions of selenium dibromide with allyl thymol and allyl carvacrol proceeded in methylene chloride at room temperature in the presence of NaHCO₃ affording bis[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] and bis[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] selenides in 90–92% yield. Similar sulfides were obtained in 70–72% yields by the reaction of sulfur dichloride in chloroform under reflux. Trihalotellanes containing the same organic moieties were synthesized from allyl thymol, allyl carvacrol and tellurium tetrachloride or tetrabromide in quantitative yields. Corresponding functionalized ditellurides were prepared in 91–92% yields by the reduction of the trichlorotellanes with sodium metabisulfite in two-phase solvent system. The comparison of reactivity of sulfur, selenium and tellurium halides in chalcogenocyclofunctionalization and distinguishing features of each reaction were discussed.     

Facile Synthesis of 5-Aryl-N-(pyrazin-2-yl)thiophene-2-carboxamides via Suzuki Cross-Coupling Reactions,Their Electronic and Nonlinear Optical Properties through DFT Calculations

Synthesis of 5-aryl-N-(pyrazin-2-yl)thiophene-2-carboxamides (4a–4n) by a Suzuki cross-coupling reaction of 5-bromo-N-(pyrazin-2-yl)thiophene-2-carboxamide (3) with various aryl/heteroaryl boronic acids/pinacol esters was observed in this article. The intermediate compound 3 was prepared by condensation of pyrazin-2-amine (1) with 5-bromothiophene-2-carboxylic acid (2) mediated by TiCl₄. The target pyrazine analogs (4a–4n) were confirmed by NMR and mass spectrometry. In DFT calculation of target molecules, several reactivity parameters like FMOs (E_HOMO, E_LUMO), HOMO–LUMO energy gap, electron affinity (A), ionization energy (I), electrophilicity index (ω), chemical softness (σ) and chemical hardness (η) were considered and discussed. Effect of various substituents was observed on values of the HOMO–LUMO energy gap and hyperpolarizability. The p-electronic delocalization extended over pyrazine, benzene and thiophene was examined in studying the NLO behavior. The chemical shifts of ¹H NMR of all the synthesized compounds 4a–4n were calculated and compared with the experimental values.     

Direct reductive amination and selective 1,2-reduction of α,β-unsaturated aldehydes and ketones by NaBH4 using H3PW12O40 as catalyst

A simple and convenient procedure for direct reductive amination of aldehydes and ketones with sodium borohydride is described. The reaction has been carried out in methanol in the presence of a catalytic amount of H₃PW₁₂O₄₀ (0.5 mol %). α,β-Unsaturated aldehydes and ketones can be easily converted into the corresponding allyl alcohols by reaction with H₃PW₁₂O₄₀ (0.5 mol %)/NaBH₄.     

A catalyst-free protocol for direct oxidative esterification of alcohols and aldehydes

A fast, simple, and efficient protocol for the direct conversion of alcohols and aldehydes to methyl ester has been developed using TsNBr₂ without any catalyst. The one pot reaction proceeds in the presence of a base at room temperature in methanol, to produce the corresponding methyl ester in high yield within a short time.     

Vibrational spectra of α-Ge(HPO4)2·H2O compound

We have measured Raman and infrared spectra of α-Ge(HPO₄)₂·H₂O compound at room temperature. The analysis of vibrational modes indicated the presence of two non-equivalent HPO₄²⁻ units in agreement with ³¹P nuclear magnetic resonance measurements. A tentative assignment of all the observed modes is proposed based on the previous works reported for other hydrogenphosphate-based compounds.     

New N-nitrosoamines. 2. Transformations of tetrahydro-1,3-oxazines into nitrates of N-nitrosoamino alcohols

The reactions of HNO₃ with tetrahydro-1,3-oxazines 1a—c produced by aminomethylation of diketopiperazine, isatin, and succinimide, respectively, afforded nitrates of amino alcohols [RCH₂NH₂(CH₂)₃ONO₂]⁺NO₃ ^– (4a—c) whose subsequent N-nitrosation (NaNO₂, AcOH) gave nitrates of N-nitrosoamino alcohols RCH₂N(NO)(CH₂)₃ONO₂ (5a—c). The structures of compound 5b,c were established by X-ray diffraction analysis.     

Synthesis,Antibacterial, and Antioxidant Evaluation of Novel Series of Condensed Thiazoloquinazoline with Pyrido,Pyrano, and Benzol Moieties as Five- and Six-Membered Heterocycle Derivatives

A novel synthesis of thiazolo[2,3-b]quinazolines 4(a–e), pyrido[2′,3′:4,5]thiazolo[2,3-b]quinazolines {5(a–e), 6(a–e), and 7(a–e)}, pyrano[2′,3′:4,5]thiazolo[2,3-b]quinazolines 8(a–e), and benzo[4,5]thiazolo[2,3-b]quinazoloine9(a–e) derivatives starting from 2-(Bis-methylsulfanyl-methylene)-5,5-dimethyl-cyclohexane-1,3-dione 2 as efficient α,α dioxoketen dithioacetal is reported and the synthetic approaches of these types of compounds will provide an innovative molecular framework to the designing of new active heterocyclic compounds. In our study, we also present optimization of the synthetic method along with a biological evaluation of these newly synthesized compounds as antioxidants and antibacterial agents against the bacterial strains, like S. aureus, E. coli, and P. aeruginosa. Among all the evaluated compounds, it was found that some showed significant antioxidant activity at 10 μg/mL while the others exhibited better antibacterial activity at 100 μg/mL. The results of this study showed that compound 6(c) possessed remarkable antibacterial activity, whereas compound 9(c) exhibited the highest efficacy as an antioxidant. The structures of the new synthetic compounds were elucidated by elemental analysis, IR, ¹H-NMR, and ¹³C-NMR.     

First Report of Fruit Rot of Cherry and Its Control Using Fe2O3 Nanoparticles Synthesized in Calotropis procera

Cherry is a fleshy drupe, and it is grown in temperate regions of the world. It is perishable, and several biotic and abiotic factors affect its yield. During April–May 2021, a severe fruit rot of cherry was observed in Swat and adjacent areas. Diseased fruit samples were collected, and the disease-causing pathogen was isolated on PDA. Subsequent morphological, microscopic, and molecular analyses identified the isolated pathogen as Aspergillus flavus. For the control of the fruit rot disease of cherry, iron oxide nanoparticles (Fe₂O₃ NPs) were synthesized in the leaf extract of Calotropis procera and characterized. Fourier transform infrared (FTIR) spectroscopy of synthesized Fe₂O₃ NPs showed the presence of capping and stabilizing agents such as alcohols, aldehydes, and halo compounds. X-ray diffraction (XRD) analysis verified the form and size (32 nm) of Fe₂O₃ NPs. Scanning electron microscopy (SEM) revealed the spinal-shaped morphology of synthesized Fe₂O₃ NPs while X-ray diffraction (EDX) analysis displayed the occurrence of main elements in the samples. After successful preparation and characterization of NPs, their antifungal activity against A. flavus was determined by poison technique. Based on in vitro and in vivo antifungal activity analyses, it was observed that 1.0 mg/mL concentration of Fe₂O₃ can effectively inhibit the growth of fungal mycelia and decrease the incidence of fruit rot of cherry. The results confirmed ecofriendly fungicidal role of Fe₂O₃ and suggested that their large-scale application in the field to replace toxic chemical fungicides.     

1,3,4-Oxadiazole N-Mannich Bases: Synthesis,Antimicrobial, and Anti-Proliferative Activities

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a–l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a–d, respectively. The in vitro inhibitory activity of compounds 4a–l and 5a–d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5–8 μg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.     

A structure, conductivity and dielectric properties investigation of A3CoNb2O9 (A=Ca, Sr, Ba) triple perovskites

The room temperature structures as well as the temperature-dependent conductivity and dielectric properties of the A₃CoNb₂O₉ (A=Ca²⁺, Sr²⁺ and Ba²⁺) triple perovskites have been carefully investigated. A constrained modulation wave approach to Rietveld structure refinement is used to determine their room temperature crystal structures. Correlations between these crystal structures and their physical properties are found. All three compounds undergo insulator to semiconductor phase transitions as a function of increasing temperature. The hexagonal Ba₃CoNb₂O₉ compound acts as an insulator at room temperature, while the monoclinic Ca₃CoNb₂O₉ compound is already a semiconductor at room temperature. The measured dielectric frequency characteristics of the A=Ba compound are excellent.     

Novel Mannich bases with strong carbonic anhydrases and acetylcholinesterase inhibition effects: 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2(3H)-benzoxazolones

In this study, a new series of Mannich bases, 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2( 3H )-benzoxazolones ( 1a–g ), were synthesized by the Mannich reaction. Inhibitory effects of the newly synthesized compounds towards carbonic anhydrases (CAs) and acetylcholinesterase (AChE) enzymes were evaluated to find out new potential drug candidate compounds. According to the inhibitory activity results, K_i values of the compounds 1 and 1a–g were in the range of 12.3 ± 1.2 to 154.0 ± 9.3 nM against hCA I, and they were in the range of 8.6 ± 1.9 to 41.0 ± 5.5 nM against hCA II. Ki values of acetazolamide (AZA) that was used as a reference compound were 84.4 ± 8.4 nM towards hCA I and 59.2 ± 4.8 nM towards hCA II. K_i values of the compounds 1 and 1a–g were in the range of 35.2 ± 2.0 to 158.9 ± 33.5 nM towards AChE. K_i value of Tacrine (TAC), the reference compound, was 68.6 ± 3.8 nM towards AChE. Furthermore, docking studies were done with the most potent compounds 1d , 1g , and 1f (in terms of hCA I, hCA II, and AChE inhibition effects, respectively) to determine the binding profiles of the series with these enzymes. Additionally, the prediction of ADME profiles of the compounds pointed out that the newly synthesized compounds had desirable physicochemical properties as lead compounds for further studies.     

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug–drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a–c exhibited an IC₅₀(AChE) = 2.9–1.4 µM, IC₅₀(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ₄₂ aggregation. Conjugates 3 had no effect on Aβ₄₂ self-aggregation, whereas compounds 5c–e (m = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2–2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood–brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c–e appear promising for future optimization and development as multitarget anti-AD agents.     

Potential COVID-19 Drug Candidates Based on Diazinyl-Thiazol-Imine Moieties: Synthesis and Greener Pastures Biological Study

A novel series of 1-aryl-N-[4-phenyl-5-(arylazo)thiazol-2-yl)methanimines has been synthesized via the condensation of 2-amino-4-phenyl-5-arylazothiazole with various aromatic aldehydes. The synthesized imines were characterized by spectroscopic techniques, namely ¹H and ¹³C-NMR, FTIR, MS, and Elemental Analysis. A molecular comparative docking study for 3a–f was calculated, with reference to two approved drugs, Molnupiravir and Remdesivir, using 7BQY (M^pro; PDB code 7BQY; resolution: 1.7 A°) under identical conditions. The binding scores against 7BQY were in the range of −7.7 to −8.7 kcal/mol for 3a–f. The high scores of the compounds indicated an enhanced binding affinity of the molecules to the receptor. This is due to the hydrophobic interactions and multi-hydrogen bonds between 3a–f ligands and the receptor’s active amino acid residues. The main aim of using in silco molecular docking was to rank 3a–f with respect to the approved drugs, Molnupiravir and Remdesivir, using free energy methods as greener pastures. A further interesting comparison presented the laydown of the ligands before and after molecular docking. These results and other supporting statistical analyses suggested that ligands 3a–f deserve further investigation in the context of potential therapeutic agents for COVID-19. Free-cost, PASS, SwissADME, and Way2drug were used in this research paper to determine the possible biological activities and cytotoxicity of 3a–f.     

A Novel One‐Pot Conversion of Allyl Alcohols into Primary Allyl Halides Mediated by Acetyl Halide

A new and simple method for the synthesis of the primary allyl chlorides and bromides 9 – 16 from the secondary or tertiary allyl alcohols 3 – 8 and acyl halide was developed (Scheme 2, Table 1). Non‐commercially available secondary and tertiary allyl alcohols were synthesized from the related ketones and aldehydes via the addition of vinylmagnesium chloride. Mechanistic studies indicate that the alcohols were first acetylated by the acetyl halide and then protonated prior to substitution by the halide, Cl^? or Br^?, via an S_N2′ reaction, to yield the primary halides (Scheme 5).     

Synthesis of Novel N-Acylhydrazones and Their C-N/N-N Bond Conformational Characterization by NMR Spectroscopy

In this article, a synthesis of N’-(benzylidene)-2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazides and their structural interpretation by NMR experiments is described in an attempt to explain the duplication of some peaks in their ¹H- and ¹³C-NMR spectra. Twenty new 6-methyl-1H-pyrazolo[3,4-b]quinoline substituted N-acylhydrazones 6(a–t) were synthesized from 2-chloro-6-methylquinoline-3-carbaldehyde (1) in four steps. 2-Chloro-6-methylquinoline-3-carbaldehyde (1) afforded 6-methyl-1H-pyrazolo[3,4-b]quinoline (2), which upon N-alkylation yielded 2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetate (3). The hydrazinolysis of 3 followed by the condensation of resulting 2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazide (4) with aromatic aldehydes gave N-acylhydrazones 6(a–t). Structures of the synthesized compounds were established by readily available techniques such as FT-IR, NMR and mass spectral studies. The stereochemical behavior of 6(a–t) was studied in dimethyl sulfoxide-d₆ solvent by means of ¹H NMR and ¹³C NMR techniques at room temperature. NMR spectra revealed the presence of N’-(benzylidene)-2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazides as a mixture of two conformers, i.e., E_(C=N)(N-N) synperiplanar and E_(C=N)(N-N) antiperiplanar at room temperature in DMSO-d₆. The ratio of both conformers was also calculated and E_{(C=N) (N-N)} syn-periplanar conformer was established to be in higher percentage in equilibrium with the E_{(C=N) (N-N)} anti-periplanar form.     

Facile one-pot synthesis of 2-arylbenzothiazoles catalyzed by H3PO4/TiO2-ZrO2 (1/1) under solvent-free conditions

A highly efficient and simple protocol for the preparation of 2-arylbenzothiazoles through condensation of 2-aminothiophenol and different aldehydes in the presence of H₃PO₄/TiO₂-ZrO₂(1/1)-cetyl pyridinium bromide (CPB) is described. The reaction proceeded under mild and solvent-free conditions to afford 2-arylbenzothiazole derivatives. In this method, the title compounds were obtained in good to excellent yields and short reaction times. The structures of synthesized products were identified by infrared, ¹H NMR, ¹³C NMR, and mass spectroscopy.     

Synthesis,Molecular Docking Studies and In Silico ADMET Screening of New Heterocycles Linked Thiazole Conjugates as Potent Anti-Hepatic Cancer Agents

Thiazoles are important scaffolds in organic chemistry. Biosynthesis of thiazoles is considered to be an excellent target for the design of novel classes of therapeutic agents. In this study, a new series of 2-ethylidenehydrazono-5-arylazothiazoles 5a–d and 2-ethylidenehydrazono-5-arylazo- thiazolones 8a–d were synthesized via the cyclocondensation reaction of the appropriate hydrazonyl halides 4a–d and 7a–d with ethylidene thiosemicarbazide 3, respectively. Furthermore, the thiosemicarbazide derivative 3 was reacted with different bromoacetyl compounds 10–12 to afford the respective thiazole derivatives 13–15. Chemical composition of the novel derivatives was established on bases of their spectral data (FTIR, ¹H-NMR, ¹³C-NMR and mass spectrometry) and microanalytical data. The newly synthesized derivatives were screened for their in vitro anti-hepatic cancer potency using an MTT assay. Moreover, an in silico technique was used to assess the interaction modes of the compounds with the active site of Rho6 protein. The docking studies of the target Rho6 with the newly synthesized fourteen compounds showed good docking scores with acceptable binding interactions. The presented results revealed that the newly synthesized compounds exhibited promising inhibition activity against hepatic cancer cell lines (HepG2).     

New Pyrimidine-5-Carbonitriles as COX-2 Inhibitors: Design,Synthesis, Anticancer Screening,Molecular Docking,and In Silico ADME Profile Studies

Two series of cyanopyrimidine hybrids were synthesized bearing either benzo[d]imidazole, benzo[d]oxazole, benzo[d]thiazole, and benzo[b]thiophene derivatives via methylene amino linker 3a–3d (Formula A) or various sulphonamide phenyl moieties 5a–5d (Formula B) at the C-2 position. All compounds’ cyclooxygenase COX-2 inhibitory activities were evaluated, and all synthesized compounds demonstrated potent activity at minimal concentrations, with IC₅₀ values in the submicromolar range. Compounds 3b, 5b, and 5d were discovered to be the most active pyrimidine derivatives, with the highest COX-2 percent inhibition and IC₅₀ values being nearly equal to Celecoxib and approximately 4.7-, 9.3-, and 10.5-fold higher than Nimesulide. Furthermore, the pyrimidine derivatives 3b, 5b, and 5d demonstrated anticancer activity comparable to or better than doxorubicin against four cell lines, i.e., MCF-7, A549, A498, and HepG2, with IC₅₀ values in nanomolar in addition to low cytotoxicity on the normal W38-I cell line. The effect of compound 5d on cell cycle progression and apoptosis induction was investigated, and it was found that compound 5d could seize cell growth at the sub-G1 and G2/M phases, as well as increase the proportion of early and late apoptotic rates in MCF-7 cells by nearly 13- and 60-fold, respectively. Moreover, in silico studies for compounds 3b, 5b, and 5d revealed promising findings, such as strong GIT absorption, absence of BBB permeability, nil-to-low drug–drug interactions, good oral bioavailability, and optimal physicochemical properties, indicating their potential as promising therapeutic candidates.     

Design,Synthesis and Biological Assessment of Rhodanine-Linked Benzenesulfonamide Derivatives as Selective and Potent Human Carbonic Anhydrase Inhibitors

A novel series of twenty-five rhodamine-linked benzenesulfonamide derivatives (7a–u and 9a–d) were synthesized and screened for their inhibitory action against four physiologically relevant human (h) carbonic anhydrase (CA) isoforms, namely hCA I, hCA II, hCA IX, and hCA XII. All the synthesized molecules showed good to excellent inhibition against all the tested isoforms in the nanomolar range due to the presence of the sulfonamide as a zinc binding group. The target compounds were developed from indol-3-ylchalcone-linked benzenesulfonamide where the indol-3-ylchalcone moiety was replaced with rhodanine-linked aldehydes or isatins to improve the inhibition. Interestingly, the molecules were slightly more selective towards hCA IX and XII compared to hCA I and II. The most potent and efficient ones against hCA I were 7h (K_I 22.4 nM) and 9d (K_I 35.8 nM) compared to the standard drug AAZ (K_I 250.0 nM), whereas in case of hCA II inhibition, the derivatives containing the isatin nucleus as a tail were preferred. Collectively, all compounds were endowed with better inhibition against hCA IX compared to AAZ (K_I 25.8 nM) as well as strong potency against hCA XII. Finally, these newly synthesized molecules could be taken as potential leads for the development of isoform selective hCA IX and XII inhibitors.     

RuCl3-DCHA Catalyst System: A Selective Aerobic Oxidation of Primary Benzylic Alcohols Under Mild Conditions

The aerobic oxidation of benzylic alcohols to their corresponding aldehydes was performed in a RuCl₃ · 3H₂O–dicyclohexylamine (DCHA) catalyst system under ambient atmosphere at room temperature. It is noteworthy that the RuCl₃ · 3H₂O–DCHA system displayed a preference for the primary versus secondary benzylic alcohols in both intermolecular and intramolecular competition experiments.