Synthesis, in Vitro Cholinesterase Inhibition, Molecular Docking, DFT, and ADME Studies of Novel 1,3,4-Oxadiazole-2-Thiol Derivatives.

A series of 1,3,4-oxadiazole-2-thiol derivatives bearing various alkyl or aryl moieties were designed, synthesized, and characterized using modern spectroscopic methods to yield 17 compounds (6a-6q) that were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in the search for 'lead' compounds for Alzheimer's disease treatment (AD). The compounds 6q, 6p, 6k, 6o, and 6l showed inhibitory capability against AChE and BChE, with IC50 values ranging from 11.73±0.49 to 27.36±0.29 µM for AChE and 21.83±0.39 to 39.43±0.44 µM for BChE, inhibiting both enzymes within a limited range. The SAR ascertained that the substitution of the aromatic moiety had a profound effect on the AChE and BChE inhibitory potential as compared to the aliphatic substitutions which were supported by the molecular docking studies. The drug-likeness of the most synthesized compounds was confirmed by in silico ADME investigations. These results were additionally supplemented by the molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps got from DFT calculations. ESP maps expose that on all structures, there are two potential binding sites conquered by the most positive and most negative districts.

Unraveling the Electrical and Magnetic Properties of Layered Conductive Metal-Organic Framework With Atomic Precision.

This paper describes structural elucidation of a layered conductive metal-organic framework (MOF) material Cu3 (C6 O6 )2 by microcrystal electron diffraction with sub-angstrom precision. This insight enables the first identification of an unusual π-stacking interaction in a layered MOF material characterized by an extremely short (2.73 Å) close packing of the ligand arising from pancake bonding and ordered water clusters within pores. Band structure analysis suggests semiconductive properties of the MOF, which are likely related to the localized nature of pancake bonds and the formation of a singlet dimer of the ligand. The spin of CuII within the Kagomé arrangement dominates the paramagnetism of the MOF, leading to strong geometrical magnetic frustration.

Synthesis, characterization, and computational study of copper bipyridine complex [Cu (C18H24N2) (NO3)2] to explore its functional properties.

In the present study, copper (II) complex of 4, 4'-di-tert-butyl-2,2'-bipyridine [Cu (C18H24N2) (NO3)2], 1 is investigated through its synthesis and characterization using elemental analysis technique, infra-red spectroscopy, and single-crystal analysis. The compound 1 crystallizes in orthorhombic space group P212121. The copper atom in the mononuclear complex is hexa coordinated through two nitrogen and four oxygen atoms from bipyridine ligand and nitrate ligands. The thermal analysis depicts the stability of the entitled compound up to 170 °C, and the decomposition takes place in different steps between 170 and 1000 °C. Furthermore, quantum chemical techniques are used to study optoelectronic, nonlinear optical, and therapeutic bioactivity. The values of isotropic and anisotropic linear polarizabilities of compound 1 are calculated as 41.65 × 10-24 and 23.02 × 10-24 esu, respectively. Likewise, the static hyperpolarizability is calculated as 47.92 × 10-36 esu using M06 functional compared with para-nitroaniline (p-NA) and found several times larger than p-NA. Furthermore, the antiviral potential of compound 1 is studied using molecular docking technique where intermolecular interactions are checked between the entitled compound and two crucial proteins of SARS-CoV-2 (COVID-19). Our investigation indicated that compound 1 interacts more vigorously to spike protein than main protease (MPro) due to its better binding energy of -9.60 kcal/mol compared with -9.10 kcal/mol of MPro. Our current study anticipated that the above-entitled coordination complexes could be potential candidates for optoelectronic properties and their biological activity.

Synthesis, Thermal, Structural Analyses, and Photoluminescent Properties of a New Family of Malonate-Containing Lanthanide(III) Coordination Polymers.

Five new Lanthanide(III) complexes of malonic acid (HOOC-CH2-COOH); {[Gd(C3H2O4)(H2O)4]·NO3} n (1), {[Tb(C3H2O4)(H2O)4]·NO3} n (2), {[Ho(C3H2O4)(H2O)4]·NO3} n (3), [Er(C3H2O4)(C3H3O4)(H2O)2] n (4), and {[Eu2(C3H2O4)2(C3H3O4)2(H2O)6]·4H2O} n (5) were synthesized and characterized by elemental, infrared spectral, and thermal analyses. The structures of compounds 1-5 were determined by single crystal X-ray diffraction technique. The X-ray analysis reveals that compounds 1, 2, and 3 are isostructural and crystallized in the orthorhombic space group Pmn21. The lanthanide(III) ions are coordinated by four carboxylate and four water oxygen atoms adopting a distorted square antiprism geometry. The LnO8 square antiprisms are linked into infinite layers by malonate (C3H2 O 4 2 - ) dianions sandwiching sheets of nitrate counter ions. Compound 4 contains ErO8 square antiprisms linked into a two-dimensional network by hydrogen malonate (C3H3 O 4 - ) anions and malonate dianions. The europium complex, 5 is dinuclear having the two europium(III) ions (Eu1 and Eu2) bridged by carboxylate groups of hydrogen malonate ligands. The europium ions in 5 are nine-coordinate and exhibit a distorted monocapped square antiprism geometry. All the structures are consolidated by O-H⋯ O hydrogen bonds. The photoluminescence spectra of 1-5 exhibit characteristic emissions in the visible region. The IR spectra and thermal data are consistent with the structural results. The room-temperature effective magnetic moments for 1-4 are in good agreement with those expected for the free ions, while the data for 5 indicates that low-lying excited states contribute to the observed moment. The compound 1 was further subjected to quantum computational calculations to explore its optoelectronic properties including; density of states (DOS), dielectric function, refractive index, extinction coefficient, and absorption spectrum, to highlight the possible applications of such materials in the optoelectronics.

Novel pyridine-2,4,6-tricarbohydrazide thiourea compounds as small key organic molecules for the potential treatment of type-2 diabetes mellitus: In vitro studies against yeast α- and ß-glucosidase and in silico molecular modeling.

A range of novel pyridine-2,4,6-tricarbohydrazide thiourea compounds (4a-i) were synthesized in good to excellent yields (63-92%). The enzyme inhibitory potentials of these compounds were investigated against α- and ß-glucosidases because these enzymes play a crucial role in treating type-2 diabetes mellitus (T2DM). As compared to the reference compound acarbose (IC50 38.22 ± 0.12 µM), compounds 4i (IC50 25.49 ± 0.67 µM), 4f (IC50 28.91 ± 0.43 µM), 4h (IC50 30.66 ± 0.52 µM), and 4e (IC50 35.01 ± 0.45 µM) delivered better inhibition against α-glucosidase and were quite inactive/completely inactive against ß-glucosidase. The structure-activity relationship of these compounds was developed and elaborated with the help of molecular docking studies.

Organocatalyzed and mechanochemical solvent-free synthesis of novel and functionalized bis-biphenyl substituted thiazolidinones as potent tyrosinase inhibitors: SAR and molecular modeling studies.

Eluding the involvement of solvents in organic synthesis and introducing environment friendly procedures can control environmental problems. A facile and an efficient solvent free mechanochemical method (grinding) is achieved to synthesize novel bis-biphenyl substituted thiazolidinones using non-toxic and cheap N-acetyl glycine (NAG). Organocatalytic condensation of a series of Schiff's bases bearing different substituents with thioglycolic acid produces a variety of thiazolidinones derivatives in good to excellent yield. In vitro inhibition studies against mushroom tyrosinase of these thiazolidinone analogues revealed that many of them possessed good to excellent tyrosinase inhibition at low micro-molar concentrations. In particular, six compounds exhibited potent inhibitory potential with IC50 values ranging from 0.61 ± 0.31 to 21.61 ± 0.11 µM as compared with that of standard kojic acid (IC50 6.04 ± 0.11 µM). Further molecular docking studies revealed that the thiazolidinones moiety plays a key role in the inhibition mechanism by well fitting into the enzyme bounding pocket.

An Efficient Synthesis of bi-Aryl Pyrimidine Heterocycles: Potential New Drug Candidates to Treat Alzheimer's Disease.

A series of 13 novel pyrimidine-based sulfonamides 6a-m were synthesized in short periods of time under microwave conditions in good to excellent yield (54-86%). The chemical structures of these heterocycles consist of a central pyrimidine ring having a phenyl group and pyrimidine groups with sulfonamide motifs. The enzyme inhibitory potential of these compounds was investigated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) because these enzymes play a crucial role in the treatment of Alzheimer's disease. As compared to the reference compound eserine (IC50 = 0.04 ± 0.0001 µM for AChE and IC50 = 0.85 ± 0.0001 µM for BChE), the IC50 values of the synthesized compounds ranged from 3.73 ± 0.61 µM to 57.36 ± 0.22 µM for AChE and 4.81 ± 0.16 µM to 111.61 ± 0.53 µM for BChE. Among these tested compounds, 6j having a -CH3 group was found to be the most potent one against both enzymes (AChE, IC50 = 3.73 ± 0.61 µM; BChE, IC50 = 4.81 ± 0.16 µM). Quantitative structure-activity relationship (QSAR) and molecular docking studies of the synthesized compounds were also performed.

Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: Synthesis, biological evaluation and molecular modeling studies.

A series of new biphenyl bis-sulfonamide derivatives 2a-3p were synthesized in good to excellent yield (76-98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC50 0.04 ± 0.0001 µM for AChE) and (IC50 0.85 ± 0.0001 µM for BChE), the IC50 values of these compounds were ranged from 2.27 ± 0.01 to 123.11 ± 0.04 µM for AChE and 7.74 ± 0.07 to <400 µM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC50 2.27 ± 0.01 µM), whereas 3g exhibited the highest inhibition for BChE (IC50 7.74 ± 0.07 µM). Structure-activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies.

Pyridine sulfonamide as a small key organic molecule for the potential treatment of type-II diabetes mellitus and Alzheimer's disease: In vitro studies against yeast α-glucosidase, acetylcholinesterase and butyrylcholinesterase.

This paper presents the efficient high yield synthesis of novel pyridine 2,4,6-tricarbohydrazide derivatives (4a-4i) along with their α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities. The enzymes inhibition results showed the potential of synthesized compounds in controlling both type-II diabetes mellitus and Alzheimer's disease. In vitro biological investigations revealed that most of compounds were more active against yeast α-glucosidase than the reference compound acarbose (IC50 38.25±0.12µM). Among the tested series the compound 4c bearing 4-flouro benzyl group was noted to be the most active (IC50 25.6±0.2µM) against α-glucosidase, and it displayed weak inhibition activities against AChE and BChE. Compound 4a exhibited the most desired results against all three enzymes, as it was significantly active against all the three enzymes; α-glucosidase (IC50 32.2±0.3µM), AChE (IC50 50.2±0.8µM) and BChE (IC50 43.8±0.8µM). Due to the most favorable activity of 4a against the tested enzymes, for molecular modeling studies this compound was selected to investigate its pattern of interaction with α-glucosidase and AChE targets.

Stability indicating RP-HPLC method for simultaneous determination of piroxicam and ofloxacin in binary combination.

A simple and precise RP-HPLC method was developed for simultaneous determination of piroxicam and ofloxacin in pharmaceutical formulations and human serum. Optimum separations of piroxicam, ofloxacin and stress-induced degradation products were achieved by use of Hypersil BDS C8 column (250 x 4.6mm, 5 µm). The mobile phase was a mixture of acetonitrile: 0.012M K2HPO4: 0.008M sodium citrate (both buffers mixed and pH adjusted to 2.8) (50:25:25 v/v/v) delivered at flow rate of 1.5 mL min⁻¹ using DAD at 254 nm. Response was linear function of concentration over the ranges of 70-130 mg mL⁻¹ for piroxicam and ofloxacin (r² ≥ 0.999). The method efficiently separated the analytical peaks from degradation products with acceptable tailing and resolution. The developed method was successfully used for concurrent analysis of piroxicam and ofloxacin in pharmaceutical formulations, human serum and in vitro drug interaction studies.

Novel pyridine-2,4,6-tricarbohydrazide derivatives: design, synthesis, characterization and in vitro biological evaluation as α- and ß-glucosidase inhibitors.

A range of novel pyridine 2,4,6-tricarbohydrazide derivatives (4a-4h) were synthesized and its biological inhibition towards α- and ß-glucosidases was studied. Most of the compounds demonstrate to be active against α-glucosidase, and quite inactive/completely inactive against ß-glucosidase. A number of compounds were found to be more active against α-glucosidase than the reference compound acarbose (IC50 38.25±0.12µM); being compound 4d with the p-hydroxy phenyl motive the most active (IC50 20.24±0.72µM). Molecular modeling studies show the interactions of compound 4d with the active site of target α-glucosidase kinase.

Novel synthesis of dihydropyrimidines for α-glucosidase inhibition to treat type 2 diabetes: in vitro biological evaluation and in silico docking.

A convenient and efficient new method has been established for the synthesis of dihydropyrimidines by inexpensive and non-toxic N-acetyl glycine (NAG) catalysed reaction of aromatic aldehydes with ethyl acetoacetate and urea/thiourea. This method is applicable for various substituted aldehydes as well as urea and thiourea. It has also been used to synthesize bicyclic oxygen-bridged pyrimidine derivatives (4d, 4j). The biological assay revealed that the majority of compounds synthesized displayed modest inhibitory activity against α-glucosidase at low micro-molar concentrations. Molecular docking studies were also performed on the most active compound, 4f (with IC50 value 112.21±0.97 µM), to show the enzyme - inhibitor interactions.

2-Chloro-6-(2,3-di-chloro-benzene-sulfonamido)-benzoic acid.

In the title compound, C13H8Cl3NO4S, the aromatic rings are oriented at a dihedral angle of 68.94 (1)° and the mol-ecule adopts a V-shape. An intra-molecular N-H⋯O inter-action generates a six-membered S(6) ring motif. In the crystal, pairs of O-H⋯O hydrogen bonds involving the carb-oxy group link the mol-ecules into inversion dimers with an R 2 (2)(8) motif. N-H⋯O and non-classical C-H⋯O inter-actions connect the mol-ecules, forming sheets propagating in (100).

Anilinium-3-carboxyl-ate 3-carb-oxy-anilinium nitrate.

The title compound, C7H8NO2(+)·NO3(-)·C7H7NO2, exists in the form of a protonated dimer of two anilinium-3-carboxyl-ate mol-ecules related by an inversion center, and a nitrate anion located on a twofold rotation axis. The bridging H atom occupies, with equal probability, the two sites associated with the carboxyl atoms. In addition to the strong O-H⋯O hydrogen bond, in the crystal, the various units are linked via N-H⋯O and C-H⋯O hydrogen bonds forming a three-dimensional structure.

3-Chloro-4-[2-(4-chloro-benzyl-idene)hydrazinyl-idene]-1-methyl-3,4-dihydro-1H-2λ(6),1-benzothia-zine-2,2-dione.

In the title compound, C16H13Cl2N3O2S, the dihedral angle between the aromatic rings is 6.62 (2)° and the C=N-N=C torsion angle is 176.2 (4)°. The thia-zine ring shows an envelope conformation, with the S atom displaced by 0.633 (6) Šfrom the mean plane of the other five atoms (r.m.s. deviation = 0.037 Å). The Cl atom is an an axial conformation and is displaced by 2.015 (6) Šfrom the thia-zine ring plane. In the crystal, mol-ecules are linked by C-H⋯O inter-actions, generating a three-dimensional network. Very weak aromatic π-π stacking inter-actions [centroid-centroid separations = 3.928 (2) Å] are also observed.

6-Bromo-1-methyl-4-[2-(1-phenyl-ethyl-idene)hydrazinyl-idene]-3,4-dihydro-1H-2λ(6),1-benzothia-zine-2,2-dione.

In the title compound, C(17)H(16)BrN(3)O(2)S, the dihedral angle between the aromatic rings is 1.24 (15)° and the C=N-N=C torsion angle is 167.7 (3)°. The conformation of the thia-zine ring is an envelope, with the S atom displaced by 0.805 (3) Šfrom the mean plane of the other five atoms (r.m.s. deviation = 0.027 Å). In the crystal, C-H⋯O inter-actions link the mol-ecules into C(10) [010] chains. A weak C-H⋯π inter-action is also observed.

3-Chloro-1-methyl-4-[2-(3-phenyl-allyl-idene)hydrazinyl-idene]-3,4-dihydro-1H-2λ(6),1-benzothia-zine-2,2-dione.

In the title compound, C(18)H(16)ClN(3)O(2)S, the dihedral angle between the aromatic rings is 4.81 (2)° and the alkyl chain takes on an extended conformation [N-C-C-C = 179.2 (4)°]. The conformation of the thia-zine ring is an envelope, with the S atom displaced by -0.805 (3) Šfrom the mean plane of the other five atoms (r.m.s. deviation = 0.046 Å). The Cl atom is an axial conformation and is displaced by 1.761 (4) Šfrom the thia-zine ring plane. In the crystal, inversion dimers linked by pairs of C-H⋯O inter-actions generate R(2) (2)(20) loops and further C-H⋯O hydrogen bonds link the dimers into (001) sheets. Weak aromatic π-π stacking inter-actions [centroid-centroid separations = 3.870 (3) and 3.883 (3) Å] are also observed.

2-(Naphthalene-2-sulfonamido)-3-phenyl-propanoic acid.

In the title compound, C(19)H(17)NO(4)S, the phenyl ring and the naphthalene ring system are oriented at a dihedral angle of 4.12 (2)° and the mol-ecule adopts a U-shaped conformation. The C(c)-C-N-S (c = carb-oxy) torsion angle is 90.98 (15)°. In the crystal, mol-ecules are linked by O-H⋯O and N-H⋯O hydrogen bonds, resulting in (100) chains incorporating centrosymmetric R(2) (2)(14) and R(2) (2)(10) loops. Weak aromatic π-π stacking is also observed [centroid-centroid separations = 3.963 (2) and 3.932 (2) Å].

N,N,N',N'-Tetra-methyl-ethylene-diammonium tetra-chlorido-zincate.

The asymmetric unit of the title compound, (C6H18N2)[ZnCl4], consists of one tetra-chlorido-zincate anion and two half-N,N,N'N'-tetra-methyl-ethylenedi-ammonium cations. Each of the two di-ammonium cations is located about an inversion center and one of them is disordered over two sets of sites in a 0.780 (17):0.220 (17) ratio. The Zn(II) atom has a slightly distorted tetra-hedral coordination environment. The cations and anions are connected via N-H⋯Cl hydrogen bonds into chains extending along [0-11].

Simultaneous RP-HPLC determination of sparfloxacin and dexamethasone in pharmaceutical formulations

The present study describes the development and subsequent validation of simple and accurate stability indicating RP-HPLC method for the determination of sparfloxacin and dexamethasone in pharmaceutical formulations in the presence of their stress-induced degradation products. Both the drugs and their stress-induced degradation products were separated within 10 minutes using C8 column and mixture of methanol and 0.02 M phosphate buffer pH 3.0 (60:40 v/v, respectively) as mobile phase at 270 nm using diode array detector. Regression analysis showed linearity in the range of 15-105 µg/mL for sparfloxacin and 5-35 µg/mL for dexamethasone. All the analytes were adequately resolved with acceptable tailing. Peak purity of the two drugs was also greater than 0.9999, showing no co-elution peaks. The developed method was applied for simultaneous determination of sparfloxacin and dexamethasone in pharmaceutical formulations for stability studies.

O presente estudo descreve o desenvolvimento e a subsequente validação de indicador de estabilidade simples e acurada por RP-HPLC para a determinação de esparfloxacino e dexametasona em formulações farmacêuticas na presença de produtos de degradação induzidos por estresse. Tanto os fármacos quanto os produtos de degradação induzidos pelo estresse foram separados em 10 minutos, utilizando coluna C8 e mistura de methanol e tampão fosfato 0,02 M, pH 3,0 (60:40 v/v, respectivamente) como fase móvel e detector de arranjo de diodo a 270 nm, A análise de regressão mostrou linearidade na faixa de 15-105 µg/mL para esparfloxacino e 5-35 µg/mL para a dexametsona. Todos os analitos foram resolvidos adequadamente com tailing aceitável. O pico de pureza dos dois foi maior que 0.9999, não mostrando picos de co-eluição. O método desenvolvido foi aplicado para a determinação simultânea de esparfloxacino e dexametasona em formulações farmacêuticas e para estudos de estabilidade.