Crystal structure of 2,4-di-amino-5-(4-hy-droxy-3-meth-oxy-phen-yl)-8,8-dimethyl-6-oxo-6,7,8,9-tetra-hydro-5H-chromeno[2,3-b]pyridine-3-carbo-nitrile-di-methyl-formamide-water (1/1/1).

In the structure of the title compound, C22H22N4O4·C3H7NO·H2O, the entire tricyclic system is approximately planar except for the carbon atom bearing the two methyl groups; the meth-oxy-phenyl ring is approximately perpendicular to the tricycle. All seven potential hydrogen-bond donors take part in classical hydrogen bonds. The main mol-ecule and the DMF combine to form broad ribbons parallel to the a axis and roughly parallel to the ab plane; the water mol-ecules connect the residues in the third dimension.

Synthesis and crystal structure of N-phenyl-2-(phenyl-sulfan-yl)acetamide.

N-Phenyl-2-(phenyl-sulfan-yl)acetamide, C14H13NOS, was synthesized and structurally characterized. In the crystal, N-H⋯O hydrogen bonding leads to the formation of chains of mol-ecules along the [100] direction. The chains are linked by C-H⋯π inter-actions, forming a three-dimensional network. The crystal studied was twinned by a twofold rotation around [100].

Novel synthesis of new triazine sulfonamides with antitumor, anti-microbial and anti-SARS-CoV-2 activities.

Novel approach for synthesizing triazine sulfonamide derivatives is accomplished via reacting the sulfaguanidine derivatives with N-cyanodithioiminocarbonate. Further reaction of the novel triazine sulfonamide analogues with various secondary amines and anilines generated various substituted triazine sulfonamide analogues of promising broad-spectrum activities including anti-microbial, anti-tumor, and anti-viral properties. The in vitro anti-proliferative activities of most of the novel compounds were evaluated on the NCI-60 cell line panel. The antifungal and antibacterial activities of the compounds were also estimated. The anti-viral activity against SARS CoV-2 virus was performed using MTT cytotoxicity assay to evaluate the half-maximal cytotoxic concentration (CC50) and inhibitory concentration 50 (IC50) of a representative compound from the novel triazine sulfonamide category. Compound 3a demonstrated potent antiviral activity against SARS-CoV-2 with IC50 = 2.378 µM as compared to the activity of the antiviral drug remdesivir (IC50 = 10.11 µM). Our results indicate that, upon optimization, these new triazine sulfonamides could potentially serve as novel antiviral drugs.

Crystal structure of 4-(benzo[d]thia-zol-2-yl)-1,2-dimethyl-1H-pyrazol-3(2H)-one.

In the title compound, C12H11N3OS, the inter-planar angle between the pyrazole and benzo-thia-zole rings is 3.31 (7)°. In the three-dimensional mol-ecular packing, the carbonyl oxygen acts as acceptor to four C-H donors (with one H⋯O as short as 2.25 Å), while one methyl hydrogen is part of the three-centre system H⋯(S, O). A double layer structure parallel to (01) can be recognized as a subsection of the packing.

Crystal structure of 2-[(5-amino-1-tosyl-1H-pyrazol-3-yl)-oxy]-1-(4-meth-oxy-phen-yl)ethan-1-one 1,4-dioxane monosolvate.

In the structure of the title compound, C19H19N3O5S·C4H8O2, the two independent dioxane mol-ecules each display inversion symmetry. The pyrazole ring is approximately parallel to the aromatic ring of the oxy-ethanone group and approximately perpendicular to the tolyl ring of the sulfonyl substituent. An extensive system of classical and 'weak' hydrogen bonds connects the residues to form a layer structure parallel to (201), within which dimeric subunits are conspicuous; neighbouring layers are connected by classical hydrogen bonds to dioxanes and by 'weak' hydrogen bonds from Htol-yl donors.

An unexpected tautomer: synthesis and crystal structure of N-[6-amino-4-(methyl-sulfan-yl)-1,2-di-hydro-1,3,5-triazin-2-yl-idene]benzenesulfonamide.

The title compound, C10H11N5O2S2, consists of an unexpected tautomer with a protonated nitro-gen atom in the triazine ring and a formal exocyclic double bond C=N to the sulfonamide moiety. The ring angles at the unsubstituted nitro-gen atoms are narrow, at 115.57 (12) and 115.19 (12)°, respectively, whereas the angle at the carbon atom between these N atoms is very wide, 127.97 (13)°. The inter-planar angle between the two rings is 79.56 (5)°. The mol-ecules are linked by three classical hydrogen bonds, forming a ribbon structure. There are also unusual linkages involving three short contacts (< 3 Å) from a sulfonamide oxygen atom to the C-NH-C part of a triazine ring.

Naphthyl cyanoketene N,S-acetals in glycoside synthesis: a new preparative route to a new class of N-naphthylcyanoacrylamide thioglycosides and their conversions to naphthyl-pyrazole hybrids.

The novel N-naphthylcyanoacrylamide thioglycosides 4 were readily prepared by the reaction of N-napthylcyanoacetamide 1 with aryl isothiocyanates in the presence of potassium hydroxide, followed by coupling of the produced salts 2 with 2,3,4,6-tetra-O-acetyl-α-d-gluco- and galacto-pyranosyl bromides 3. The N-naphthyl acrylamide thioglycoside 12 was prepared by the reaction of N-napthylcyanoacetamide 1 with glucose isothiocyante 10 in the presence of potassium hydroxide, followed by alkylation of the produced salt 11 with methyl iodide. The reaction of thioglycoside compounds 4 with hydrazines afforded the corresponding naphthyl-pyrazole hybrids.

Crystal structure of 2-{[5-(methyl-sulfan-yl)-4-phenyl-4H-1,2,4-triazol-3-yl]meth-yl}benzo[d]thia-zole.

In the structure of the title compound, C17H14N4O2, the triazole ring exhibits inter-planar angles of 63.86 (2) and 76.96 (2)° with the phenyl and benzo-thia-zole planes, respectively. The C-C-C angle at the methyl-ene group is rather wide at 114.28 (4)°. The packing involves three borderline C-H⋯N contacts, two of which combine to form layers parallel to ac, and a pairing of the triazole rings across an inversion centre [inter-planar distance of 3.1852 (2) Å].

Crystal structure of 5-(ß-d-gluco-pyran-osyl-thio)-N-(4-methyl-phen-yl)-1,3,4-thia-diazol-2-amine.

In the structure of the title compound, C15H19N3O5S2, the bond lengths at the linking sulfur atom are significantly different [1.7473 (17) and 1.811 (2) Å], and the angle at the exocyclic nitro-gen atom is wide at 128.45 (18)°. The inter-planar angle between the tolyl and thia-diazole rings is 9.2 (1)°. The complex hydrogen-bonding pattern, involving five donors and five acceptors, can be broken down into a one-dimensional ribbon parallel to the b axis, involving hydrogen bonds of the sugar residues only, and a two-dimensional layer structure parallel to the ab plane, based on the N-H⋯O and O-H⋯N hydrogen bonds.

Novel Fluorescent Benzothiazolyl-Coumarin Hybrids as Anti-SARS-COVID-2 Agents Supported by Molecular Docking Studies: Design, Synthesis, X-ray Crystal Structures, DFT, and TD-DFT/PCM Calculations.

This study revealed the design and preparation of new 3-(benzo[d]thiazol-2-yl)-2H-chromen-2-one derivatives 9a-h. The structures of the synthesized products were elucidated by their spectroscopic data and X-ray crystallography for compounds 9a and 9d. The prepared new compounds were measured for their fluorescence, and a good result indicated that the emission efficiency was decreased by increasing the electron-withdrawing groups from the unsubstituted compound 9a to the highly substituted derivative 9h (2 Br heavy atoms). On the other hand, the B3LYP/6-311G** theoretical level of theory was used to optimize the quantum mechanical calculations of the geometrical characteristics and energy of the novel compounds 9a-h under study. The electronic transition was investigated using the TD-DFT/PCM B3LYP approach, which uses time-dependent density functional calculations. Moreover, the compounds exhibited nonlinear optical properties (NLO) and a small HOMO-LUMO energy gap, which makes them easy to polarize. Furthermore, the acquired infrared spectra were compared with the expected harmonic vibrations of the substances 9a-h. On the other hand, binding energy analyses of compounds 9a-h with human corona virus nucleocapsid protein Nl63 (PDB ID: 5epw) were predicted using molecular docking and virtual screening tools. The results showed a promising binding and how these potent compounds were inhibiting the COVID-19 virus. Compound 9h was the most active anti-COVID-19 agent among all the synthesized benzothiazolyl-coumarin derivatives, as it forms five bonds. The presence of the two bromine atoms in its structure was responsible for the potent activity.

Crystal structure of N-[3-(benzo[d]thia-zol-2-yl)-6-bromo-2H-chromen-2-yl-idene]-4-methyl-benzenamine.

The title compound, C23H15BrN2OS, was the unexpected product in an attempted synthesis of the isomeric 3-(benzo[d]thia-zol-2-yl)-6-bromo-1-p-tolyl-quinolin-2(1H)-one. The Cchromene=N-C angle is wide [125.28 (8)°]. The benzo-thia-zole and chromene ring systems are almost coplanar, with their planes parallel to (10); the toluene ring system is rotated by ca 40° out of the chromene plane. The mol-ecular packing involves layers with π-stacking, borderline 'weak' hydrogen bonds and possible C-H⋯π contacts.

Crystal structure of 3-(benzo[d]thia-zol-2-yl)-6-methyl-2H-chromen-2-one.

The mol-ecule of the title compound, C17H11NO2S, is almost planar, with an inter-planar angle of 3.01 (3)° between the benzo-thia-zole and chromene ring systems. A short intra-molecular S⋯O=C contact of 2.727 (2) Šis observed. The crystal packing involves a layer structure parallel to (211), containing dimeric inversion-symmetric units connected by a 'weak' C-H⋯O=C hydrogen bond.

Crystal structures of three homologues with increasing ring size: 2-meth-oxy-4-(thio-phen-2-yl)-5,6,7,8-tetra-hydro-quinoline-3-carbo-nitrile, 2-meth-oxy-4-(thio-phen-2-yl)-6,7,8,9-tetra-hydro-5H-cyclo-hepta-[b]pyridine-3-carbo-nitrile and 2-meth-oxy-4-(thio-phen-2-yl)-5,6,7,8,9,10-hexa-hydrocyclo-octa[b]pyridine-3-carbo-nitrile.

The title compounds, C15H14N2OS (1a), C16H16N2OS (1b), and C17H18N2OS (1c), form a homologous series in which the size of the saturated ring increases from six- to eight-membered (with four, five and six methyl-ene groups respectively). For 1b and 1c, the central (CH2) n moieties are all displaced to the same side of their ring, and the CH2-CH2-CH2 angles are much wider than the standard sp 3 value; a database search indicates that these are general features of such ring systems. For 1a, the thio-phene ring lies with the sulfur atom on the opposite side of the Cthio-phene-Cpyridine bond to the cyano group, in contrast to 1b and 1c. For each compound, the packing may be described in terms of two 'weak' C-H⋯N hydrogen bonds, which link the mol-ecules to form one-dimensional (1a, 1c) or three-dimensional (1b) assemblies.

Purine analogs: synthesis, evaluation and molecular dynamics of pyrazolopyrimidines based benzothiazole as anticancer and antimicrobial CDK inhibitors.

Cyclin dependent kinases (CDKs) enzymes regulate cell proliferation and transcriptional processes and can be considered as important targets for the development of anticancer and antimicrobial drugs. In this work, novel benzothiazolyl pyrazolopyrimidine carboxamide and benzothiazolyl pyrazolopyrimidine carbonitrile derivatives were synthesized and characterized. The synthetic process was carried out via the reaction of ylidine benzothiazole derivatives with pyrazolocarboxamide and pyrazolocarbonitrile through a Michael addition pathway. Docking studies were done against CDK2 and CDK9 enzymes and revealed that compound 8a showed high free energy of binding against CDK2 (-8.10 kcal/mol) while compound 15a showed the highest free energy of binding against CDK2 (-8.16 kcal/mol) and CDK9 (-7.87 kcal/mol). Molecular dynamics simulations were conducted to compare the stability of binding of the most active compound 15a and the potent reference drugs roscovitine and dinaciclib. A CDK enzyme assay was done against CDK2 and CDK9 for the previously mentioned top-ranked compounds, 8a and 15a. It was found that compound 15a was the most potent inhibitor for both enzymes with IC50 of 127 ± 1.01 nM and 65 ± 0.50 nM. The anticancer activity of the synthesized compounds was also determined by NCI against 60 cell lines. Compound 8a showed the highest cytotoxic activity against a large number of the tested cell lines. The antimicrobial activity of the synthesized compounds was determined against various gram positive and gram-negative bacteria as well as fungi. The results showed that compound 15a had the strongest antibacterial activity.

Synthesis, Physicochemical Properties and Molecular Docking of New Benzothiazole Derivatives as Antimicrobial Agents Targeting DHPS Enzyme.

The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial agents remains an important drug target. From this perspective, new derivatives of benzothiazole were synthesized and evaluated for their antimicrobial activity and ability to inhibit the DHPS enzyme. The synthesis was carried out by the reaction of benzothiazole N-arylsulphonylhydrazone with N-aryl-2-cyano-3-(dimethylamino)acrylamide, N-aryl-3-(dimethylamino)prop-2-en-1-one, arylaldehydes or diazonium salt of arylamine derivatives, which led to the formation of N-arylsulfonylpyridones 6a-d (yield 60-70%) and 12a-c (yield 50-60%),N-(2-(benzo[d]thiazole-2-yl)-3-arylacryloyl-4-methylsulfonohydrazide 14a-c (yield 60-65%), 4-(benzo[d]thiazole-2-yl)-5-aryl-1H-pyrazol-3(2H)-one 16a-c (yield 65-75%), and N'-(2-(benzo[d]thiazol-2-yl)-2-(2-arylhydrazono)acetyl)-4-arylsulfonohydrazide 19a-e (yield 85-70%). The antimicrobial evaluations resulted into a variety of microbial activities against the tested strains. Most compounds showed antimicrobial activity against S. aureus with an MIC range of 0.025 to 2.609 mM. The most active compound, 16c, exhibited superior activity against the S. aureus strain with an of MIC 0.025 mM among all tested compounds, outperforming both standard drugs ampicillin and sulfadiazine. The physicochemical-pharmacokinetic properties of the synthesized compounds were studied, and it was discovered that some compounds do not violate rule of five and have good bioavailability and drug-likeness scores. The five antimicrobial potent compounds with good physicochemical-pharmacokinetic properties were then examined for their inhibition of DHPS enzyme. According to the finding, three compounds, 16a-c, had IC50 values comparable to the standard drug and revealed that compound 16b was the most active compound with an IC50 value of 7.85 µg/mL, which is comparable to that of sulfadiazine (standard drug) with an IC50 value of 7.13 µg/mL. A docking study was performed to better understand the interaction of potent compounds with the binding sites of the DHPS enzyme, which revealed that compounds 16a-c are linked by two arene-H interactions with Lys220 within the PABA pocket.

4-Amino-5-(4-bromo-benzo-yl)-3-(benzo[d]thia-zol-2-yl)-2-[(2',3',4',6'-tetra-O-acetyl-ß-d-galacto-pyran-osyl-)sulfanyl]-thio-phene.

In the title compound, C32H29BrN2O10S3, the benzo-thia-zole and thio-phene ring systems subtend an inter-planar angle of 7.43 (12)°. The NH2 group forms intra-molecular hydrogen bonds to Nthia-zole and Ocarbon-yl. The Sgalactose-Cthio-phene bond is short [1.759 (2) Å]. The mol-ecules are connected to form ribbons parallel to the b axis by two 'weak' hydrogen bonds and a short Namino⋯Sgalactose contact.

3-(Benzo[d]thia-zol-2-yl)-2H-chromen-2-one.

In the title compound, C16H9NO2S, the inter-planar angle is 6.47 (6)°. An intra-molecular S⋯O=C contact of 2.727 (2) Šis observed. The packing is determined by several types of weak inter-action ('weak' hydrogen bonds, S⋯S contacts and π-π stacking).

Medicinal Chemistry of Pyrazolopyrimidine Scaffolds Substituted with Different Heterocyclic Nuclei.

BACKGROUND: Medicinal chemistry of pyrazolopyrimidine scaffolds substituted with different heterocyclic nuclei has attracted great attention due to their wide range of biological activities that have been reported. Pyrazolopyrimidine scaffold is an important privileged heterocycle nucleus in drug discovery. METHODS: All pharmacological activities of pyrazolopyrimidine scaffold have been mentioned, such as anticancer, anti-inflammatory, antihypertensive, antitubercular, antiviral, antibacterial, antifungal, antidiabetic, and anti-obesity agents. In addition, it was used in both osteoporosis and neurological disorders. The difference in potency and bioavailability of pyrazolopyrimidine derivatives refers to the substituent groups that can increase the activity against specific targets and enhance their selectivity. RESULTS: This review provides an overview of different synthetic pathways, structure activity relationships, and preclinical studies of pyrazolopyrimidine scaffolds substituted with a variety of heterocyclic nuclei, as well as it provides a discussion on the significant biological findings of these important scaffolds. In addition, it provides some insights on the different macromolecular targets that pyrazolopyrimidine scaffold can effectively work on, such as; cyclin dependent kinases; CDK2, CDK7, and CDK9, checkpoint kinases; CHK1 and CHK2 and their correlation with the anticancer activity, PI3Kα, transient receptor potential canonical 6, B-Raf kinase, Interleukin- 1 receptor-associated kinase 4, B-cell lymphoma 6, TRKA-C kinase, potent kDa ribosomal protein S6 kinase, colon cancer cell line (CaCo-2), domain receptor kinase (KDR), HepG-2 carcinoma cell, FLT3. The antibacterial activity against B. subtilis and E. coli and antifungal activity against C. albicans, C. tropicalis, A. niger, and A. clavatus are discussed. CONCLUSION: This review provides an overview of the different pharmacological activities of the pyrazolopyrimidine scaffold and its correlation with chemical structure. Some exciting new developments in pyrazolopyrimidine scaffolds are also presented in this review.

Novel Thiophene Thioglycosides Substituted with the Benzothiazole Moiety: Synthesis, Characterization, Antiviral and Anticancer Evaluations, and NS3/4A and USP7 Enzyme Inhibitions.

Novel derivatives of benzothiazole-2-thiophene S-glycoside were synthesized and tested for their antiviral and anticancer potency and NS3/4A and USP7 enzyme inhibitions. The ring system was formed by first synthesizing new derivatives of 5-mercaptothiophene substituted with the benzothiazole moiety, followed by coupling with various halo sugar derivatives. New compounds were tested in vitro for the cytotoxic effect on five types of normal cell lines and for antiviral activity using a plaque reduction assay against CBV4, HSV-1, HCVcc genotype 4 viruses, HAV HM 175, and HAdV7. Notably, three compounds demonstrated substantial IC50, CC50, and SI values against HSV-1 with a viral reduction of 80% or more. Two substances have demonstrated a reduction of more than 50% in CBV4 and HCVcc viruses. The effectiveness of the compounds against HSV-1 and HCVcc was tested for their capability to inhibit NS3/4A protease and USP7 enzyme. Additionally, a panel of 60 human cancer cells was used to investigate the ability of the newly synthesized compounds to inhibit the in vitro tumor growth. The results revealed that two compounds, 6a and 6c, have an inhibitory effect on most cancer types, whereas 6d and 6f inhibited only three and two cell lines, respectively.

Crystal structure of 2-amino-5,6,7,8-tetra-hydro-7,7-dimethyl-4-(naphthalen-2-yl)-5-oxo-4H-chromene-3-carbo-nitrile.

In the title compound, C22H20N2O2, both six-membered rings of the fused heterocyclic system display envelope conformations; the two carbon atoms bearing the methyl groups and the naphthyl substituent both lie outside the planes of the other atoms of each ring. In the crystal, the amino group forms hydrogen bonds of the types N-H⋯O=C and N-H⋯N≡C, leading to the formation of a double layer structure propagating parallel to the bc plane. Weak C-H⋯O and C-H⋯π inter-actions may reinforce the layers.