Structures and biological activity of three 2-(pyridin-2-yl)-1H-benzimidazole derivatives.

Two new 2-(pyridin-2-yl)-1H-benzimidazole derivatives, namely, 2-(4-phenoxypyridin-2-yl)-1H-benzimidazole, C18H13N3O, and 2-[4-(4-fluorophenoxy)pyridin-2-yl]-1H-benzimidazole, C18H12FN3O, were synthesized and characterized by NMR spectroscopy. Crystal structure, biological activity and ADME analyses were performed for these two new compounds and a third compound, namely, 5,6-dimethyl-2-[4-(4-phenylpiperazin-1-yl)pyridin-2-yl]-1H-benzimidazole methanol monosolvate, C24H25N5·CH3OH, the synthesis of which had been described previously. All three compounds have a similar chain hydrogen-bonding pattern. One of them (the fluorophenoxy derivative) showed good antimicrobial activity against Gram-positive bacteria. The ADME analysis indicates that the compounds could be good drug candidates.

N'-Substituted 4-Phenylpicolinohydrazonamides with Thiosemicarbazone Moiety as New Potential Antitubercular Agents: Synthesis, Structure and Evaluation of Antimicrobial Activity.

Three new 4-phenylpicolin derivatives with a thiosemicarbazone structure were synthesized and evaluated for tuberculostatic activity. The compounds were obtained by the condensation of methyl 4-phenylpicolonimidate with the corresponding cycloalkylamino-1-carbothiohydrazides. The 1H NMR temperature spectra obtained showed proton lability at the nitrogen atom N2, and X-ray crystallography confirmed the zwitterionic structure of all products. ADME calculations indicate that the compounds can be tested as future drugs. All compounds were absorbed in the gastrointestinal tract. All compounds also showed very good tuberculostatic activity (MIC 3.1-12.5 µg/mL). Derivative 1b showed the best selectivity for M. tuberculosis compared to the other pathogenic species tested. The study has allowed the emergence of imine derivative 1b as a good structure for further optimization in the search for antitubercular drugs.

Influence of Incorporation of Different dn-Electron Metal Cations into Biologically Active System on Its Biological and Physicochemical Properties.

Three new compounds, namely [HL]2+[CuCl4]2-, [HL]2+[ZnCl4]2-, and [HL]2+[CdCl4]2- (where L: imipramine) were synthesized and their physicochemical and biological properties were thoroughly investigated. All three compounds form isostructural, crystalline systems, which have been studied using Single-Crystal X-ray diffraction analysis (SC-XRD) and Fourier-transform infrared spectroscopy (FTIR). The thermal stability was investigated using thermogravimetric analysis (TGA) and melting points for all compounds have been determined. Magnetic measurements were performed in order to study the magnetic properties of the compounds. The above mentioned techniques allowed us to comprehensively examine the physicochemical properties of the newly obtained compounds. The biological activity was investigated using the number of Zebrafish tests, as it is one of the most common models for studying the impact of newly synthesized compounds on the central nervous system (CNS), since this model is very similar to the human CNS.

The First Insight Into the Supramolecular System of D,L-α-Difluoromethylornithine: A New Antiviral Perspective.

Targeting the polyamine biosynthetic pathway by inhibiting ornithine decarboxylase (ODC) is a powerful approach in the fight against diverse viruses, including SARS-CoV-2. Difluoromethylornithine (DFMO, eflornithine) is the best-known inhibitor of ODC and a broad-spectrum, unique therapeutical agent. Nevertheless, its pharmacokinetic profile is not perfect, especially when large doses are required in antiviral treatment. This article presents a holistic study focusing on the molecular and supramolecular structure of DFMO and the design of its analogues toward the development of safer and more effective formulations. In this context, we provide the first deep insight into the supramolecular system of DFMO supplemented by a comprehensive, qualitative and quantitative survey of non-covalent interactions via Hirshfeld surface, molecular electrostatic potential, enrichment ratio and energy frameworks analysis visualizing 3-D topology of interactions in order to understand the differences in the cooperativity of interactions involved in the formation of either basic or large synthons (Long-range Synthon Aufbau Modules, LSAM) at the subsequent levels of well-organized supramolecular self-assembly, in comparison with the ornithine structure. In the light of the drug discovery, supramolecular studies of amino acids, essential constituents of proteins, are of prime importance. In brief, the same amino-carboxy synthons are observed in the bio-system containing DFMO. DFT calculations revealed that the biological environment changes the molecular structure of DFMO only slightly. The ADMET profile of structural modifications of DFMO and optimization of its analogue as a new promising drug via molecular docking are discussed in detail.

A Proline-Based Tectons and Supramolecular Synthons for Drug Design 2.0: A Case Study of ACEI.

Proline is a unique, endogenous amino acid, prevalent in proteins and essential for living organisms. It is appreciated as a tecton for the rational design of new bio-active substances. Herein, we present a short overview of the subject. We analyzed 2366 proline-derived structures deposited in the Cambridge Structure Database, with emphasis on the angiotensin-converting enzyme inhibitors. The latter are the first-line antihypertensive and cardiological drugs. Their side effects prompt a search for improved pharmaceuticals. Characterization of tectons (molecular building blocks) and the resulting supramolecular synthons (patterns of intermolecular interactions) involving proline derivatives, as presented in this study, may be useful for in silico molecular docking and macromolecular modeling studies. The DFT, Hirshfeld surface and energy framework methods gave considerable insight into the nature of close inter-contacts and supramolecular topology. Substituents of proline entity are important for the formation and cooperation of synthons. Tectonic subunits contain proline moieties characterized by diverse ionization states: -N and -COOH(-COO-), -N+ and -COOH(-COO-), -NH and -COOH(-COO-), -NH+ and -COOH(-COO-), and -NH2+ and -COOH(-COO-). Furthermore, pharmacological profiles of ACE inhibitors and their impurities were determined via an in silico approach. The above data were used to develop comprehensive classification, which may be useful in further drug design studies.

Synthesis, Structural Characterization, and Biological Activity of New Pyrazolo[4,3-e][1,2,4]triazine Acyclonucleosides.

A series of new pyrazolo[4,3-e][1,2,4]triazine acyclonucleosides 2-5 and 8 were prepared and evaluated for their anticancer activity against human cancer cell lines (MCF-7, K-562) and CDK2/E, as well as Abl protein kinases inhibitors. Lipophilicity of the compounds was determined using C-18 and immobilized artificial membrane (IAM) chromatography. In order to confirm the molecular structures and synthesis pathway of new acyclonucleosides, X-ray analysis was performed for model compound 3. Theoretical calculations at the DFT/B3LYP/6-311++G(d,p) level were used for the characterization of electronic structures of 1-8. The potential antiviral activity of acyclonucleosides 2-8 was tested in silico using molecular docking method.

Synthesis, In Vitro Screening and Docking Studies of New Thiosemicarbazide Derivatives as Antitubercular Agents.

A series of thiosemicarbazide derivatives was designed and synthesized by reaction of carboxylic acid hydrazide with isothiocyanates. The molecular structures of the investigated thiosemicarbazides were confirmed and characterized by spectroscopic analysis. The conformational preference of carbonylthiosemicarbazide chain and intra- and intermolecular interactions in the crystalline state were characterized using X-ray analysis. The antituberculosis activity of the target compounds were tested in vitro against four Mycobacterium strains: M. H37Ra, M. phlei, M. smegmatis, M. timereck. The most active compounds were those with 2-pyridine ring. They exhibited lower minimal inhibitory concentration (MIC) values in the range 7.81⁻31.25 µg/mL in comparison to the other isomers. Compound 5 had activity against M. smegmatis at a concentration of 7.81 µg/mL whereas compound 2 had activity against all tested strains at a concentration of 15.625 µg/mL. The molecular docking studies were performed for investigated compounds using the Mycobacterium tuberculosis glutamine synthetase MtGS as their molecular target.

Polysubstituted 3-trifluoromethylpyrazoles: regioselective (3 + 2)-cycloaddition of trifluoroacetonitrile imines with enol ethers and functional group transformations.

Non-catalysed addition of trifluoroacetonitrile imines to enol ethers provided fully regioselectively (3 + 2)-cycloadducts, which either spontaneously or via Brønsted acid-induced elimination of ROH molecules led to the formation of 3-trifluoromethylated pyrazoles. In the case of 2,3-dihydrofuran, the respective bicyclic intermediate was isolated and its structure was confirmed by X-ray analysis. Using the developed protocol the synthesis of a known antitumor compound SC-560 was performed in 45% yield. Subsequent functionalisations of selected 4-(ω-hydroxyalkyl)pyrazoles at C(5) through lithiation/addition, cross-coupling reactions or via intramolecular Pd-catalysed C-H arylations opened up an access to polysubstituted pyrazoles including unusual tricyclic systems comprising 7-membered rings (oxepane, thiepane and azepane) as the central unit.

Synthesis, Structure and Antiproliferative Activity of New pyrazolo[4,3- e]triazolo[4,5-b][1,2,4]triazine Derivatives.

BACKGROUND: Triazoles and their fused derivatives are an important class of compounds that exhibit interesting biological properties, such as antiasthmatic, antimicrobial, antifungal, analgesic, antiallergic, antiinflammatory, herbicidal, plant growth regulative activity, and anti-HIV-1 activities. Moreover, anticancer activity of 1,2,4-triazole containing derivatives has been documented. Due to the fact a convenient approach toward polycyclic frameworks containing fused 1,2,4-triazoles was described. OBJECTIVE: The objective of this article is the synthesis of new pyrazolo[4,3-e]triazolo[4,5- b][1,2,4]triazine derivatives with potential antiproliferative activity. METHODS: Cancer cell proliferation was analysed by means of MTT assay after 96 h treatment. IC50 was calculated using computerized linear regression analysis of quantal log doseprobit functions, according to the method of Litchfield and Wilcoxon. X-ray data were collected on the Bruker SMART APEX II CCD diffractometer; The structure was solved by direct methods using SHELXS-2013 and refined by full-matrix least-squares with SHELXL-2014/7. All calculations were performed using WINGX version 2014.1 package. RESULTS: The series of pyrazolo[4,3-e]triazolo[4,5-b][1,2,4]triazine derivatives were synthesized. MTT assay revealed that the compounds inhibited cancer cells growth at concentrations below 10 µM. The tested compounds showed higher antiproliferative activity than popular cytostatics cisplatin (lung carcinoma) and 5-fluorouracil (colon adenocarcinoma). X-ray examinations showed that final products in the crystalline phase have a linear form. CONCLUSION: In the paper we have reported the synthesis and spectroscopic analysis of new condensed tricyclic derivatives of the pyrazolo[4,3-e]triazolo[4,5-b][1,2,4]triazine. MTT analysis revealed concentration-dependent decrease in lung A549 and colon LS180 cancer cells proliferation. In order to explain the molecular mechanisms involved in anticancer activity of pyrazolo[4,3- e]triazolo[4,5-b][1,2,4]triazine derivatives, our research will be continued.

Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine H3R ligands.

As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2-21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6-8 (Ki=8.8-23.4nM range) and among them piperidine derivative 6 with Ki=8.8nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50=157 and 164nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2-4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30mg/kg at 0.5h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate "drug-likeness" of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed.

Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors.

A new series of 32 pyrimido- and 5 tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3-dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione was found to be the most potent A1 AR antagonist of the present series, showing selectivity over the other AR subtypes. The structure-activity for the obtained purinediones was established. Docking experiments of the investigated library to homology models of the human and rat A1 and A2A ARs allowed to compare the expected binding modes for selected compounds. The detailed analysis of binding cavities within individual AR subtypes indicated small but significant structural variations that may underlie the observed differences in binding affinities of purinediones at particular subtypes and species.

Discovery of nitroaryl urea derivatives with antiproliferative properties.

A series of urea derivatives bearing nitroaryl moiety has been synthesized and assayed for their potential antiproliferative activities. Some of the tested compounds displayed activity in RK33 laryngeal cancer cells and TE671 rhabdomyosarcoma cells while being generally less toxic to healthy HSF human fibroblasts cells. One compound was demonstrated to be a moderate CDK2 inhibitor with IC50 = 14.3 µM. Its structure was solved by an X-ray crystallography and molecular modelling was performed to determine structure-activity relationship. Obtained compounds constitute novel structures and generally demonstrated greater cytotoxicity in comparison to cisplatin. This study offers new structural motifs with potential for further development.

Captopril and its dimer captopril disulfide: comparative structural and conformational studies.

The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid}, C(9)H(15)NO(3)S, (1), and its dimer disulfide metabolite, 1,1'-{disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1-diyl]}bis-L-proline, C(18)H(28)N(2)O(6)S(2), (2), were determined by single-crystal X-ray diffraction analysis. Compound (1) crystallizes in the orthorhombic space group P2(1)2(1)2(1), while compound (2) crystallizes in the monoclinic space group P2(1), both with one molecule per asymmetric unit. The molecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five-membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half-chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum-energy conformational search using Monte Carlo methods in the aqueous phase reveals that the optimized conformations of the title compounds differ from those determined crystallographically, which depend on their immediate environment. Intermolecular O-H...O and relatively weak C-H...O interactions seem to be effective in both structures and, together with S-H...O and C-H...S contacts, they create three-dimensional networks.

Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors.

Non-competitive ligands of kainate receptors have focused significant attention as medicinal compounds because they seem to be better tolerated than competitive antagonists and uncompetitive blocker of these receptors. Here we present structural studies (X-ray structure determination, NMR and MS spectra) of novel indole-derived non-competitive antagonists of GluK1/GluK2 receptors, homology models of GluK1 and GluK2 receptors based on novel AMPA receptor template as well as molecular docking of ligands to their molecular targets. We find that the allosteric site is in the receptor transduction domain, in one receptor subunit, not between the two subunits as it was indicated by our earlier studies.

Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes.

In this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8-13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25µg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC90 <1µg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10-50% or even more (10b) under experimental conditions.

Novel pseudopolymorph of the active metabolite of perindopril.

The dimethyl sulfoxide hemisolvate of perindoprilat [systematic name: (1S)-2-((S)-{1-[(2S,3aS,7aS)-2-carboxyoctahydro-1H-indol-1-yl]-1-oxopropan-2-yl}azaniumyl)pentanoate dimethyl sulfoxide hemisolvate], C(17)H(28)N(2)O(5)·0.5C(2)H(6)OS, an active metabolite of perindopril, has been synthesized, structurally characterized by single-crystal X-ray diffraction and compared with its ethanol disolvate analogue [Pascard et al. (1991). J. Med. Chem. 34, 663-669]. Both compounds crystallize in the orthorhombic P2(1)2(1)2(1) space group in the same zwitterionic form, with a protonated alanine N atom and an anionic carboxylate group at the n-alkyl chain. The three structural units present in the unit cell (two zwitterions and the solvent molecule) are held together by a rich system of O-H···O, N-H···O and C-H···O hydrogen-bond contacts.

Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α1-adrenoceptor antagonistic properties.

The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α(1)-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a-18a using a crystal structure of 7. SAR analysis was performed on the basis of Barbaro's pharmacophore model and structural properties of previously investigated α(1)-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α(1)-ARs in nanomolar range (40-290 nM). The highest activities (K(i)<75 nM) were observed for compounds possessing a 2-alkoxyphenylpiperazine fragment and two methoxy substituents at the benzylidene moiety. The results indicated that chemical properties, number and positions of substituents at the 5-arylidene fragment influenced the power of α(1)-affinities as follows: 3,4-di CH(3)O>2,4-di CH(3)O>4-Cl>2,3-di CH(3)O>H>4-N(CH(3))(2).

Ethyl 2-(3-methyl-5-sulfanyl-idene-4,5-dihydro-1H-1,2,4-triazol-4-yl)acetate.

The title compound, C7H11N3O2S, exists in the 5-thioxo tautomeric form. The 1,2,4-triazoline ring is essentially planar, with a maximum deviation of 0.010 (2) Šfor the substituted N atom. The ethyl acetate substituent is almost planar, with a maximum deviation of 0.061 (4) Šfor the methyl-ene C atom of the eth-oxy group. The angle between the mean plane of this substituent and the mean plane of the 1,2,4-triazoline ring is 89.74 (8)°. In the crystal, mol-ecules are linked by a combination of N-H⋯S, C-H⋯N and C-H⋯O hydrogen bonds into chains parallel to [100].

2-(5,6-Diphenyl-1,2,4-triazin-3-yl)aniline.

The title compound, C21H16N4, obtained under standard Suzuki cross-coupling conditions, is a model compound in the synthesis and biological activity evaluation of new aza-analogues of sildenafil containing a pyrazolo-[4,3-e][1,2,4]triazine system. An N-H⋯N intra-molecular hydrogen bond involving the amino-benzene system and the 1,2,4-triazine moiety helps to establish a near coplanar orientation of the rings with a dihedral angle of 12.04 (4)°, which is believed to be necessary for the biological activity of sildenafil analogues. The 1,2,4-triazine ring is slightly distorted from planarity [r.m.s deviation = 0.0299 (11) Å] and forms dihedral angles of 58.60 (4) and 36.35 (3)° with the pendant phenyl rings. The crystal packing features bifurcated N-H⋯(N,N) hydrogen bonds linking screw-axis-related mol-ecules into chains parallel to the [010] direction and π-π inter-actions, with a centroid-centroid separation of 3.8722 (7) Šand a slippage of 1.412 (3) Å. The crystal studied was a nonmerohedral twin with a ratio of 0.707 (2):0293 (2).

5,6,7,8-Tetra-hydro-quinolin-8-one.

In the quinoline fused-ring system of the title compound, C(9)H(9)NO, the pyridine ring is planar to within 0.011 (3) Å, while the partially saturated cyclo-hexene ring adopts a sofa conformation with an asymmetry parameter ΔC(s)(C6) = 1.5 (4)°. There are no classical hydrogen bonds in the crystal structure. Mol-ecules form mol-ecular layers parallel to (100) with a distance between the layers of a/2 = 3.468 Å.