Structure-property relationship in thioxotriaza-spiro derivative: Crystal structure and molecular docking analysis against SARS-CoV-2 main protease.

Detailed structural and non-covalent interactions in thioxotriaza-spiroderivative (DZ2) are investigated by single crystal structure anslysis and computational approaches. Its results were compared with the previously reported spiroderivative (DZ1). The crystal structure analysis revealed various C-H…O, N-H…O, C-H…N and N-H…S hydrogen bonds involved in constructing several dimeric motifs to stabilize the crystal packing. The differences and similarities in the relative contribution of non-covalent interactions in DZ1 and DZ2 compounds are compared using the Hirshfeld surface analysis and 2D fingerprint plots. The binding energies of specific molecular pairs and homodimers have been obtained using molecule-molecule interaction energy calculation. The hierarchy and topology of pair-wise intermolecular interactions are visualized through energy frameworks. The nature and strength of intra and intermolecular interactions were characterized using non-covalent interaction index analysis and the quantum theory of atoms in molecule approach. Further, molecular docking of compounds (DZ1 and DZ2) with SARS-CoV-2 main protease for COVID-19 is performed. And the superposition of these ligands and inhibitor N3, which is docked into the binding pocket of 7BQY, is presented. The binding affinity of -6.7 kcal/mol is observed, attributed to hydrogen bonding and hydrophobic interactions between the ligand and the amino acid residues of the receptor.

I2-Catalyzed transformation of o-aminobenzamide to o-ureidobenzonitrile using isothiocyanates.

The present work describes an unexpected and unique protocol for the iodine catalysed synthesis of o-ureidobenzonitriles using o-aminobenzamides and isothiocyanates via intramolecular rearrangement. The metal-free route achieved here is insensitive to moisture and applicable to the synthesis of a wide variety of o-ureidobenzonitriles with excellent yields even in a scalable fashion.

Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents.

The structural modification and molecular docking-based screening approaches on thiazole-based isoindolinediones were imposed to find the novel 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives. The best fit compounds (6a-n) were synthesized and evaluated their antiproliferative activities on the prostate cancer cell lines (PC-3 & LNCaP). Among them, the compound, 6m exhibited good activity, particularly on LNCaP (IC50=5.96±1.6µM), moderately active against PC-3 cell lines as compared to bicalutamide. The compound, 6m decreased the androgen-mediated transcription of ARE-mRNA in PSA, TMPRSS2, c-myc and cyclin D1 than R-bicalutamide. The compounds, 6e and 6f were reconfirmed through single crystal XRD analysis. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. These findings may provide vital information for the development of anti-prostate cancer agents.

Crystal structure of ATP-binding subunit of an ABC transporter from Geobacillus kaustophilus.

The ATP binding cassette (ABC) transporters, represent one of the largest superfamilies of primary transporters, which are very essential for various biological functions. The crystal structure of ATP-binding subunit of an ABC transporter from Geobacillus kaustophilus has been determined at 1.77 Å resolution. The crystal structure revealed that the protomer has two thick arms, (arm I and II), which resemble 'L' shape. The ATP-binding pocket is located close to the end of arm I. ATP molecule is docked into the active site of the protein. The dimeric crystal structure of ATP-binding subunit of ABC transporter from G. kaustophilus has been compared with the previously reported crystal structure of ATP-binding subunit of ABC transporter from Salmonella typhimurium.

Crystal structure studies of NADP+ dependent isocitrate dehydrogenase from Thermus thermophilus exhibiting a novel terminal domain.

NADP(+) dependent isocitrate dehydrogenase (IDH) is an enzyme catalyzing oxidative decarboxylation of isocitrate into oxalosuccinate (intermediate) and finally the product α-ketoglutarate. The crystal structure of Thermus thermophilus isocitrate dehydrogenase (TtIDH) ternary complex with citrate and cofactor NADP(+) was determined using X-ray diffraction method to a resolution of 1.80 Å. The overall fold of this protein was resolved into large domain, small domain and a clasp domain. The monomeric structure reveals a novel terminal domain involved in dimerization, very unique and novel domain when compared to other IDH's. And, small domain and clasp domain showing significant differences when compared to other IDH's of the same sub-family. The structure of TtIDH reveals the absence of helix at the clasp domain, which is mainly involved in oligomerization in other IDH's. Also, helices/beta sheets are absent in the small domain, when compared to other IDH's of the same sub family. The overall TtIDH structure exhibits closed conformation with catalytic triad residues, Tyr144-Asp248-Lys191 are conserved. Oligomerization of the protein is quantized using interface area and subunit-subunit interactions between protomers. Overall, the TtIDH structure with novel terminal domain may be categorized as a first structure of subfamily of type IV.

Crystal structure of product-bound complex of UDP-N-acetyl-d-mannosamine dehydrogenase from Pyrococcus horikoshii OT3.

UDP-N-acetyl-d-mannosamine dehydrogenase (UDP-d-ManNAcDH) belongs to UDP-glucose/GDP-mannose dehydrogenase family and catalyzes Uridine-diphospho-N-acetyl-d-mannosamine (UDP-d-ManNAc) to Uridine-diphospho-N-acetyl-d-mannosaminuronic acid (UDP-d-ManNAcA) through twofold oxidation of NAD(+). In order to reveal the structural features of the Pyrococcus horikoshii UDP-d-ManNAcADH, we have determined the crystal structure of the product-bound enzyme by X-ray diffraction to resolution of 1.55Å. The protomer folds into three distinct domains; nucleotide binding domain (NBD), substrate binding domain (SBD) and oligomerization domain (OD, involved in the dimerization). The clear electron density of the UDP-d-ManNAcA is observed and the residues binding are identified for the first time. Crystal structures reveal a tight dimeric polymer chains with product-bound in all the structures. The catalytic residues Cys258 and Lys204 are conserved. The Cys258 acts as catalytic nucleophile and Lys204 as acid/base catalyst. The product is directly interacts with residues Arg211, Thr249, Arg244, Gly255, Arg289, Lys319 and Arg398. In addition, the structural parameters responsible for thermostability and oligomerization of the three dimensional structure are analyzed.

Crystal structures of type IIIH NAD-dependent D-3-phosphoglycerate dehydrogenase from two thermophiles.

In the L-Serine biosynthesis, D-3-phosphoglycerate dehydrogenase (PGDH) catalyzes the inter-conversion of D-3-phosphoglycerate to phosphohydroxypyruvate. PGDH belongs to 2-hydroxyacid dehydrogenases family. We have determined the crystal structures of PGDH from Sulfolobus tokodaii (StPGDH) and Pyrococcus horikoshii (PhPGDH) using X-ray diffraction to resolution of 1.77Å and 1.95Å, respectively. The PGDH protomer from both species exhibits identical structures, consisting of substrate binding domain and nucleotide binding domain. The residues and water molecules interacting with the NAD are identified. The catalytic triad residues Glu-His-Arg are highly conserved. The residues involved in the dimer interface and the structural features responsible for thermostability are evaluated. Overall, structures of PGDHs with two domains and histidine at the active site are categorized as type IIIH and such PGDHs structures having this type are reported for the first time.

Crystal structure of N-(3-hy-droxy-phenyl)succinimide.

In the title compound, C10H9NO3, the dihedral angle between the benzene and pyrrolidine rings is 53.9 (1)°. In the crystal, mol-ecules are linked through strong O-H⋯O hydrogen bonds into zigzag C(8) chains running along [010]. The chains are linked by C-H⋯π inter-actions forming sheets lying parallel to (100).

2-(3,4-Di-meth-oxy-phen-yl)-4-(thio-phen-2-yl)-2,3-di-hydro-1,5-benzo-thia-zepine.

In the title compound, C21H19NO2S2, the seven-membered thia-zepine ring adopts a slightly distorted twist boat conformation. The dihedral angle between the benzene rings is 67.4 (2)°. The mean plane of the thio-phene ring is twisted by 59.3 (2) and 87.7 (2)° from the mean planes of the benezene rings. In the crystal, inversion dimers linked by pairs of C-H⋯O hydrogen bonds generate R 2 (2)(20) loops.

1-Fluoro-4-[(E)-2-nitro-vin-yl]benzene.

The title compound, C8H6FNO2, is almost planar (r.m.s. deviation for the non-H atoms = 0.019 Å) and the conformation across the C=C bond is trans. The C and H atoms of the side chain are disordered over two sets of sites in a 0.56 (3):0.44 (3) ratio. In the crystal, mol-ecules are linked by C-H⋯O inter-actions, thus forming C(5) chains propagating in [001].

4-(4-Methyl-phen-yl)-2-(prop-2-yn-1-yl)phthalazin-1(2H)-one.

In the title compound, C18H14N2O, the dihedral angle between the methyl-phenyl ring and the phthalazone ring system (r.m.s. deviation = 0.034 Å) is 53.93 (9)°. In the crystal, mol-ecules are connected by C-H⋯O hydrogen bonds, forming chains along [101]. The chains are linked by π-π inter-actions [centroid-centroid distance 3.6990 (12) Å], forming layers parallel to (10-1).

(E)-N'-[4-(Di-methyl-amino)-benzyl-idene]-2-(4-methyl-phen-oxy)acetohydrazide.

In the title compound, C18H21N3O2, the dihedral angle between the benzene rings is 68.85 (11)°. In the crystal, the mol-ecules are linked by C-H⋯O and N-H⋯O hydrogen bonds, as well as weak C-H⋯π contacts, forming a three-dimensional supra-molecular architecture.

6,7-Dimeth-oxy-2,4-di-phenyl-quinoline.

In the title structure of the title compound, C23H19NO2, two conformationally similar mol-ecules (A and B) comprise the asymmetric unit. The dihedral angle between phenyl rings bridged by the quinoline moiety are 76.25 (8)° in mol-ecule A and 70.39 (9)° in mol-ecule B. In the crystal, the independent mol-ecules are connected by C-H⋯O hydrogen bonds and the resulting dimeric aggregates are linked by π-π [inter-centroid distance = 3.7370 (8) Å] and C-H⋯π inter-actions, forming a three-dimensional architecture.

N-(4-Methyl-phenyl-sulfon-yl)-3-nitro-benzamide.

In the title compound, C14H12N2O5S, the dihedral angle between the aromatic rings is 86.29 (1)° and the conformation between the C=O bond of the amide group and the meta-NO2 group is syn. The C-S-N-C torsion angle is -65.87 (19)° and the mol-ecule has an L-shaped conformation. In the crystal, the mol-ecules are connected into inversion dimers through pairs of N-H⋯O hydrogen bonds and C-H⋯O inter-actions forming R 2 (2)(8) and R 2 (2)(14) loops, respectively. The dimers are connected by further C-H⋯O inter-actions, thereby forming (100) sheets.

N-(4-Meth-oxy-benzo-yl)benzene-sulfon-amide.

In the title compound, C14H13NO4S, the dihedral angle between the aromatic rings is 69.81 (1)°; the dihedral angle between the planes defined by the S-N-C=O segment of the central chain and the sulfonyl benzene ring is 74.91 (1)°. In the crystal, the mol-ecules are linked by weak N-H⋯O hydrogen bonds into C(4) chains running along [100]. The mol-ecules in adjacent chains are linked by weak C-H⋯O inter-actions, generating R 2 (2) (16) dimeric pairs. Weak C-H⋯π inter-actions connect the double chains into (001) sheets.

N-(4-Meth-oxy-benzo-yl)-2-methyl-benzene-sulfonamide.

In the title compound, C15H15NO4S, the dihedral angle between the aromatic rings is 80.81 (1)° and the dihedral angle between the planes defined by the S-N-C=O fragment and the sulfonyl benzene ring is 86.34 (1)°. In the extended structure, dimers related by a crystallographic twofold axis are connected by pairs of both N-H⋯O hydrogen bonds and C-H⋯O inter-actions, which generate R 2 (2)(8) and R 2 (2)(14) loops, respectively. A weak aromatic π-π stacking inter-action is also observed [centroid-centroid separation = 3.7305 (3) Å].

2-Chloro-N-(4-meth-oxy-benzo-yl)-benzene-sulfonamide.

In the title compound, C14H12ClNO4S, the dihedral angle between the aromatic rings is 82.07 (1)° and the dihedral angle between the planes defined by the S-N-C=O fragment and the sulfonyl benzene ring is 82.46 (3)°. In the crystal, the mol-ecules are linked into C(4) chains running along [001] by strong N-H⋯O hydrogen bonds. A C-H⋯O intera-ction reinforces the [001] chains: its graph-set symbol is C(7). The chains are cross-linked into (100) sheets by further C-H⋯O inter-actions as C(6) chains along [001]. The structure also features weak π-π stacking inter-actions [centroid-centroid distances = 3.577 (1) and 3.8016 (1) Å].

N-Ethyl-2,2-dimethyl-N-(3-methyl-phen-yl)propanamide.

In the title compound, C14H21NO, the conformation across the N-C(O) bond is syn-periplanar, the C-N-C-C torsion being -5.9 (5)°. The atoms of the ethyl group attached to the N atom are disordered over two sets of sites with occupancy ratios of 0.65 (2):0.35 (2) (CH2) and 0.689 (14):0.311 (14) (CH3)are linked by very weak C-H⋯O inter-actions forming C(8) chains along [001]. C-H⋯π inter-actions link the mol-ecules along the c-axis direction.

4-(Thio-phen-2-yl)-2-[4-(tri-fluoro-meth-yl)phen-yl]-2,3-di-hydro-1,5-benzo-thia-zepine.

In the title compound, C20H14F3NS2, the seven-membered thia-zepine ring adopts a slightly distorted twist-boat conformation. The mean plane of the five-membered thio-phene ring fused to the thia-zepine ring is twisted by 32.3 (3) and 55.6 (4)° from the benzene and phenyl rings, respectively. In the crystal, inversion dimers linked by pairs of weak C-H⋯N inter-actions are observed.

(4-Fluoro-phen-yl)(2-hy-droxy-5-methyl-phen-yl)methanone.

In the title compound, C14H11FO2, the dihedral angles beteen the central C3O ketone residue and the fluoro- and hy-droxy-substituted benzene rings are 50.44 (9) and 12.63 (10)°, respectively. The planes of the benzene rings subtend a dihedral angle of 58.88 (9)° and an intra-molecular O-H⋯O hydrogen bond closes an S(6) ring. No directional inter-actions beyond van der Waals packing contacts were identified in the crystal structure.