Structure-guided fragment-based<Emphasis Type="Italic"> in silico</Emphasis> drug design of dengue protease inhibitors

An in silico fragment-based drug design approach was devised and applied towards the identification of small molecule inhibitors of the dengue virus (DENV) NS2B-NS3 protease. Currently, no DENV protease co-crystal structure with bound inhibitor and fully formed substrate binding site is available. Therefore a homology model of DENV NS2B-NS3 protease was generated employing a multiple template spatial restraints method and used for structure-based design. A library of molecular fragments was derived from the ZINC screening database with help of the retrosynthetic combinatorial analysis procedure (RECAP). 150,000 molecular fragments were docked to the DENV protease homology model and the docking poses were rescored using a target-specific scoring function. High scoring fragments were assembled to small molecule candidates by an implicit linking cascade. The cascade included substructure searching and structural filters focusing on interactions with the S1 and S2 pockets of the protease. The chemical space adjacent to the promising candidates was further explored by neighborhood searching. A total of 23 compounds were tested experimentally and two compounds were discovered to inhibit dengue protease (IC₅₀ = 7.7 μM and 37.9 μM, respectively) and the related West Nile virus protease (IC₅₀ = 6.3 μM and 39.0 μM, respectively). This study demonstrates the successful application of a structure-guided fragment-based in silico drug design approach for dengue protease inhibitors providing straightforward hit generation using a combination of homology modeling, fragment docking, chemical similarity and structural filters.     

Stabilization of a high energy molecular conformation by specific intermolecular forces, a novel planar benzylideneaniline system

The system containing six benzylideneanilines (BA) has been studied: Group 1:

Effect of the position of a methoxy substituent on the antimicrobial activity and crystal structures of 4‐methyl‐1,6‐diphenylpyrimidine‐2(1H)‐selenone derivatives

Derivatives of pyrimidine‐2(1H)‐selenone are a group of compounds with very strong antimicrobial activity. In order to study the effect of the position of the methoxy substituent on biological activity, molecular geometry and intermolecular interactions in the crystal, three derivatives were prepared and evaluated with respect to their antimicrobial activities, and their crystal structures were determined by X‐ray diffraction. The investigated compounds, namely, 1‐(X‐methoxyphenyl)‐4‐methyl‐6‐phenylpyrimidine‐2(1H)‐selenones (X = 2, 3 and 4 for 1 , 2 and 3 , respectively), C₁₈H₁₆N₂OSe, showed very strong activity against selected strains of Gram‐positive bacteria and fungi. Two compounds, 1 and 2 , crystallize in the monoclinic space group P2₁/c, while 3 crystallizes in the space group P2₁/n; 1 has two molecules in the asymmetric unit and the other two ( 2 and 3 ) have one molecule. The geometries of the investigated compounds differ slightly in the mutual orientations of the aromatic and pyrimidineselenone rings. The O atom in 1 stabilizes the conformation of the molecules via intramolecular C—H…O hydrogen bonding. The packing of molecules is determined by weak C—H…N and C—H…Se intermolecular interactions and additionally in 1 and 2 by C—H…O intermolecular interactions. The introduction of the methoxy substituent results in greater selectivity of the investigated compounds.     

Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations

Zika virus (ZIKV) has been characterized as one of many potential pathogens and placed under future epidemic outbreaks by the WHO. However, a lack of potential therapeutics can result in an uncontrolled pandemic as with other human pandemic viruses. Therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted a strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the NS2B-NS3 protease (ZIKV^pro) and NS5 RNA dependent RNA polymerase (ZIKV^RdRp) proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of the top four common bioflavonoids, viz. Rutin, Nicotiflorin, Isoquercitrin, and Hyperoside. These compounds showed substantial docking energy (−7.9 to −11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKV^pro (B:His⁵¹, B:Asp⁷⁵, and B:Ser¹³⁵) and ZIKV^RdRp (Asp⁵⁴⁰, Ile⁷⁹⁹, and Asp⁶⁶⁵) by comparison to the reference compounds, O7N inhibitor (ZIKV^pro) and Sofosbuvir inhibitor (ZIKV^RdRp). Besides, long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals stability of the respective docked poses contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKV^pro and ZIKV^RdRp against ZIKV for further experimental assessment.     

A Combined Experimental and Theoretical Electron Density Study of Intra‐ and Intermolecular Interactions in Thiourea S,S‐Dioxide

The thiourea S,S‐dioxide molecule is recognized as a zwitterion with a high dipole moment and an unusually long C? S bond. The molecule has a most interesting set of intermolecular interactions in the crystalline state—a relatively strong O???H? N hydrogen bond and very weak intermolecular C???S and N???O interactions. The molecule has C_s symmetry, and each oxygen atom is hydrogen‐bonded to two hydrogen atoms with O???H? N distances of 2.837 and 2.826 Å and angles of 176.61 and 158.38°. The electron density distribution is obtained both from Xray diffraction data at 110 K and from a periodic density functional theory (DFT) calculation. Bond characterization is made in terms of the analysis of topological properties. The covalent characters of the C? N, N? H, C? S, and S? O bonds are apparent, and the agreement on the topological properties between experiment and theory is adequate. The features of the Laplacian distributions, bond paths, and atomic domains are comparable. In a systematic approach, DFT calculations are performed based on a monomer, a dimer, a heptamer, and a crystal to see the effect on the electron density distribution due to the intermolecular interactions. The dipole moment of the molecule is enhanced in the solid state. The typical values of ρ_b and H_b of the hydrogen bonds and weak intermolecular C???S and N???O interactions are given. All the interactions are verified by the location of the bond critical point and its associated topological properties. The isovalue surface of Laplacian charge density and the detailed atomic graph around each atomic site reveal the shape of the valence‐shell charge concentration and provide a reasonable interpretation of the bonding of each atom.     

THE CRYSTAL AND MOLECULAR STRUCTURE OF THE POTENTIAL ANTIBACTERIAL AGENT 2-PYRIDYL-PHENYL SULPHONE

Abstract

Crystals of 2-pyridyl-phenyl sulphone are monoclinic, space group P2₁/c, with eight molecules in the unit cell of dimensions a = 11.781, b = 5.903, c = 29.748 Å and B = 94.13°. The dihedral angles between the best planes of the two aromatic rings are significantly different in two crystallographically independent molecules (88.4° and 71.9° for molecule A and molecule B, respectively), as well as those between the CSC plane and the pyridine ring (59.4° and 67.4°) and between the CSC plane and the phenyl ring (51.7° and 81.8°). The average bond distances of interest include C?S 1.77(1) and S?O 1.44(1) Å; among the bond angles there are CSO = 108.1(7), CSC = 105.0(6) and OSO = 118.7(6)°. The packing of the molecule in the crystal is determined by the van der Waals interactions and by two intermolecular H?O contacts of 2.43 and 2.49 Å. The observed conformation in the solid state agrees well with results of previous investigations, in the solution state, by means of dipole moment method and theoretical M.O. calculations, for the analogous di-2-pyridyl sulphone.     

Crystal Structures of Mono-, Di-, and Tri(p-tert-butyl)-thiacalix[4]arenes: Dimeric Self-inclusion Behavior

X-Ray crystal structures of the mono-, di-, and tri(p-tert-butyl)-substituted thiacalix[4]arenes (TC4As; 1, 2, and 3, respectively) have beendetermined. TC4As 1–3 adopt a cone conformation and form dimeric self-inclusion units in such a manner that phenol moieties are inserted into the cavity of each molecule. In all the crystal structures of 1–3, lateralface-to-face interactions exist between the phenol rings that do not bear a tert-butyl substituent, and seemingly, this molecular assembly stabilizes the formation of self-inclusion. TC4As 1 and 2 adopt a cone conformation with C₂ symmetry, leading to the formation of rim-to-rim intermolecular hydrogenbonds so as to link the dimeric units up and down. On the other hand, 3 adopts a regular cone conformation with C₄ symmetry to form cyclic hydrogen bonds withinthe rim part of TC4A.     

Polymorphic forms of lupane triterpenoid betulonic aldehyde (betulonal)

The lupane triterpenoid betulonic aldehyde [also known as betulonal; systematic name: lup‐20(29)‐en‐28‐al‐3‐one, C₃₀H₄₆O₂] is a product of betulin oxidation. Crystals were obtained from hexane [form (I)] and dimethyl sulfoxide [form (II)] solutions. Forms (I) and (II) are both orthorhombic. The molecular geometric parameters in the two forms are similar, but the structures are different with respect to the crystal packing. Polymorph (I) contains two independent molecules in the asymmetric unit, while polymorph (II) contains only one molecule, which has a disordered aldehyde group [the disorder ratio is 0.769 (4):0.231 (4)]. In each molecule, the six‐membered rings have chair conformations, whereas the cyclopentane ring in each molecule adopts an envelope conformation. All the rings in the lupane nucleus are trans‐fused. The extended structures of both polymorphs are stabilized by weak intermolecular C—H...O and van der Waals interactions. Weak intramolecular C—H...O interactions are also observed.     

Features of intermolecular interactions in the crystals of metal acetylacetonates

For 12 acetylacetonates of the composition M(acac) _n (n = 2, 3, or 4) and M(acac)(C₂H₄)₂ (M is a metal) the total area (⁰ S) of the faces of Voronoi-Dirichlet polyhedra (VDP) corresponding to all intermolecular contacts of one molecule in the crystal structure and the total volume of pyramids (⁰ V), whose bases are formed of such faces and the vertices are occupied by the nuclei of atoms participating in intermolecular contacts, are determined. The key features of non-bonded interactions are considered. The existence of a linear dependence of the sublimation enthalpy of acetylacetonates on the ⁰ S or ⁰ V parameters of their molecular VDP is revealed. It is shown that the sublimation enthalpy of Ga(acac)₃ requires the refinement and theoretically should be 124 kJ/mol.     

Cocaethylene,the in vivo product of cocaine and ethanol,is a narcotic more potent than its precursors

The molecular conformation and supramolecular architecture of cocaethylene [systematic name: ethyl (1R ,2R ,3S ,5S )‐3‐benzoyloxy‐8‐methyl‐8‐azabicyclo[3.2.1]octane‐2‐carboxylate], C₁₈H₂₃NO₄, have been determined for the first time. Cocaethylene is a narcotic produced in vivo when cocaine and ethanol are administered concomitantly. The intra‐ and intermolecular features of cocaethylene and its less potent narcotic precursor cocaine are very similar. The only molecular difference is in the conformation of the methyl group of the ethoxycarbonyl group. Similar to cocaine, the carboxylate atoms and the α‐C atom are coplanar in cocaethylene, but the methyl C atom of the ethyl group is bent by ca 90° away from this plane in the narcotic reported here. The main supramolecular motif is a one‐dimensional chain stabilized by weak C—H…O contacts.     

STEREOCHEMISTRY OF COMPLEXES WITH N-ALKYLATED AMINO ACIDS. VIII. CRYSTAL STRUCTURE AND CONFORMATIONAL ANALYSIS OF AQUABIS(L-N,N-DIMETHYLTHREONINATO)COPPER(II) DIHYDRATE

Abstract

The structure of blue, monoclinic (space group P2₁) crystals of aquabis(L-N,N-dimethylthreoninato)copper(II) dihydrate was determined by X-ray diffraction and refined to R = 0.030. The coordination around the copper(II) atom is distorted square-pyramidal with threonine N and O atoms in trans orientations (Cu-O 1.930(3) and 1.926(3)Å, Cu-N 2.042(3) and 2.055(3)Å, O-Cu-O 163.9, N-Cu-N 164.0°) and apical water (Cu-O(W) 2.206 Å). The shape of the coordination polyhedron was reasonably well reproduced with molecular mechanics calculations, yielding root-mean-square deviations of ten valence angles around copper to 4.5°. The calculated strain energy of the crystal conformation is about 21 kJ mol^? higher than the energy of the most stable conformer. This was tentatively attributed to the additional stabilization of molecular conformation by intermolecular hydrogen bonds in the solid state.     

A clothes‐peg‐shaped binuclear trans‐bis(2‐aminotroponato)palladium(II) complex bearing pentamethylene spacers

rac‐Bis{μ‐trans‐2,2′‐[pentane‐1,5‐diylbis(azanediyl)]ditroponato}dipalladium(II), [Pd₂(C₁₉H₂₀N₂O₂)₂], has been synthesized and fully characterized using single‐crystal X‐ray diffraction, ¹H NMR, FT–IR and mass spectroscopy. The trans coordination, vaulted structure and anti conformation have been unequivocally established from the X‐ray diffraction studies. This is the first example of a bis(aminotroponato)palladium complex. In the crystalline state, the molecule has twofold symmetry and each molecular unit undergoes intermolecular offset π‐stacking of the tropone rings to afford heterochiral interpenetrating dimers that are aligned in a lamellar manner with a herringbone packing motif.     

Qualitative and quantitative analysis of intermolecular interactions in xanthenedione derivatives

The existence of intermolecular interactions and the conformational geometry adopted by molecules are related to biological activity. Xanthenedione molecules are promising and emerging antioxidants and acetylcholinesterase inhibitors. To examine the role of different functional groups involved in the intermolecular interactions and conformational geometries adopted in xanthenediones, a series of three substituted xanthenediones have been crystallized [9‐(3‐hydroxyphenyl)‐3,3,6,6‐tetramethyl‐3,4,5,6,7,9‐hexahydro‐1H‐xanthene‐1,8(2H)‐dione, C₂₃H₂₆O₄, 9‐(5‐bromo‐2‐methoxyphenyl)‐3,3,6,6‐tetramethyl‐3,4,6,7‐tetrahydro‐2H‐xanthene‐1,8(5H,9H)‐dione, C₂₄H₂₇BrO₄, and 3,3,6,6‐tetramethyl‐9‐(pyridin‐2‐yl)‐3,4,6,7‐tetrahydro‐2H‐xanthene‐1,8(5H,9H)‐dione, C₂₂H₂₅NO₃] and their intermolecular interactions analyzed via Hirshfeld analysis. The results show that all the derivatives adopt the same structural conformation, where the central ring has a shallow boat conformation and the outer rings have a twisted boat conformation. The intermolecular interactions in the molecules are predominantly O—H…O, C—H…O and π–π interactions. The optimized structures of the derivatives from theoretical B3LYP/6‐311G** calculations show a good correlation with the experimental structures. The lattice energy involved in the intermolecular interactions has been explored using PIXELC.     

Nonperipherally Octa(butyloxy)‐Substituted Phthalocyanine Derivatives with Good Crystallinity: Effects of Metal–Ligand Coordination on the Molecular Structure,Internal Structure,and Dimensions of Self‐Assembled Nanostructures

To investigate the effects of metal–ligand coordination on the molecular structure, internal structure, dimensions, and morphology of self‐assembled nanostructures, two nonperipherally octa(alkoxyl)‐substituted phthalocyanine compounds with good crystallinity, namely, metal‐free 1,4,8,11,15,18,22,25‐octa(butyloxy)phthalocyanine H₂Pc(α‐OC₄H₉)₈ ( 1 ) and its lead complex Pb[Pc(α‐OC₄H₉)₈] ( 2 ), were synthesized. Single‐crystal X‐ray diffraction analysis revealed the distorted molecular structure of metal‐free phthalocyanine with a saddle conformation. In the crystal of 2 , two monomeric molecules are linked by coordination of the Pb atom of one molecule with an aza‐nitrogen atom and its two neighboring oxygen atoms from the butyloxy substituents of another molecule, thereby forming a Pb‐connected pseudo‐double‐decker supramolecular structure with a domed conformation for the phthalocyanine ligand. The self‐assembling properties of 1 and 2 in the absence and presence of sodium ions were comparatively investigated by scanning electronic microscopy (SEM), spectroscopy, and X‐ray diffraction techniques. Intermolecular π–π interactions between metal‐free phthalocyanine molecules led to the formation of nanoribbons several micrometers in length and with an average width of approximately 100 nm, whereas the phthalocyaninato lead complex self‐assembles into nanostructures also with the ribbon morphology and micrometer length but with a different average width of approximately 150 nm depending on the π–π interactions between neighboring Pb‐connected pseudo‐double‐decker building blocks. This revealed the effect of the molecular structure (conformation) associated with metal–ligand (Pb? N_isoindole, Pb? N_aza, and Pb? O_butyloxy) coordination on the dimensions of the nanostructures. In the presence of Na⁺, additional metal–ligand (Na? N_aza and Na? O_butyloxy) coordination bonds formed between sodium atoms and aza‐nitrogen atoms and the neighboring butyloxy oxygen atoms of two metal‐free phthalocyanine molecules cooperate with the intrinsic intermolecular π–π interactions, thereby resulting in an Na‐connected pseudo‐double‐decker building block with a twisted structure for the phthalocyanine ligand, which self‐assembles into twisted nanoribbons with an average width of approximately 50 nm depending on the intertetrapyrrole π–π interaction. This is evidenced by the X‐ray diffraction analysis results for the resulting aggregates. Twisted nanoribbons with an average width of approximately 100 nm were also formed from the lead coordination compound 2 in the presence of Na⁺ with a Pb‐connected pseudo‐double‐decker as the building block due to the formation of metal–ligand (Na? N_aza and Na? O_butyloxy) coordination bonds between additionally introduced sodium ions and two phthalocyanine ligands of neighboring pseudo‐double‐decker building blocks.     

Weak C—H...Cl—Pd interactions toward conformational polymorphism in trans‐dichloridobis(triphenylphosphane)palladium(II)

A new triclinic polymorph of the title compound, [PdCl₂(C₁₈H₁₅P)₂], has two independent molecules in the unit cell, with the Pd atoms located on inversion centres. One molecule has an eclipsed conformation, whereas the second molecule adopts a gauche conformation. The molecules with a gauche conformation are involved in weak intermolecular C—H...Cl—Pd interactions with symmetry‐related molecules. It is suggested that C—H...Cl—Pd interactions are mainly responsible for the existence of conformational differences, which contribute to the polymorph formation. In the crystal, there are layers of eclipsed and gauche molecules separated by normal van der Waals interactions.     

Mononuclear and dinuclear iron(III) compounds with β-diketonate ligands: Synthesis,magnetic behavior and DFT calculations

The synthesis, crystal structure, magnetic properties and DFT calculations of two low-nuclearity Fe(III) compounds based on β-diketonate ligand, [Fe(OMe)(BTA)₂]₂ (1) and Fe(BTA)₃ (2) (BTA = 4,4,4-trifluoro-1-phenyl-2,4-butanedione) are reported. Compound (1) is a molecular dimer in which Fe(III) ions are coordinated to two BTA ligands and bridged by two methoxide anions, while compound (2) is a trischelated Fe(III) monomer. Magnetic measurements revealed antiferromagnetic interactions in both compounds. In (1) the magnetic coupling is intramolecular, whereas in (2) it occurs via intermolecular interactions as a result of π–π stacking between the phenyl rings. DFT calculations using the broken symmetry approach were carried out to obtain the theoretical coupling constant value for both compounds and to rationalize the pathway for magnetic interactions in (2).     

7,7‐Di­chloro‐1,6‐di­methyl‐2‐oxa‐5‐thia­bi­cyclo­[4.1.0]­heptane 5,5‐dioxide and 6‐chloro‐2,3‐di­hydro‐7‐methyl‐5‐methyl­ene‐2H,3H,5H‐1,4‐dithiepine 1,1,4,4‐tetraoxide

The structures of a 2‐oxa‐5‐thia­bi­cyclo­[4.1.0]­heptane derivative, C₇H₁₀Cl₂O₃S, (I), and a 2H,3H,5H‐1,4‐dithiepine derivative, C₇H₉ClO₄S₂, (II), are reported. The six‐membered ring in (I) has an envelope conformation and the seven‐membered ring in (II) adopts a chair conformation. There are no untoward intermolecular interactions in (I), but two Cl atoms make a short intermolecular contact across an inversion centre in (II), with a Cl?Cl distance of 3.2784 (9) Å, some 0.22 Å less than the sum of the van der Waals radii.     

tert‐Butyl 5‐methoxy‐3‐pentyl­indole‐1‐carboxyl­ate

The molecule of the title compound, C₁₉H₂₇NO₃, is essentially planar, with all non‐H atoms within 0.2 Å of the nine‐membered indole plane, except for the three tert‐butyl C atoms. The C₅ pentyl chain is in an extended conformation, with three torsion angles of 179.95 (13), 179.65 (13) and −178.95 (15)° (the latter two angles include the C atoms of the C₅ chain only). Three intramolecular C—H⋯Ozdbnd;C contacts are present (C⋯O < 3.05 Å and C—H⋯O > 115°), and an intermolecular C—H⋯Ozdbnd;C contact and π–π stacking complete the intermolecular interactions.     

Conformational Polymorphism in N‐(4′‐methoxyphenyl)‐ 3‐bromothiobenzamide

Three conformational polymorphs of N‐(4′‐methoxyphenyl)‐3‐bromothiobenzamide, yellow α, orange β, and yellow γ, have been identified by single‐crystal X‐ray diffraction. The properties and structure of the polymorphs were examined with FT Raman, FTIR (ATR), and UV/Vis spectroscopy, as well as differential scanning calorimetry. Computational data on rotational barriers in the isolated gas‐phase molecule indicate that the molecular conformation found in the α form is energetically preferred, but only by around 2 kJ mol^?1 over the γ conformation. The planar molecular structure found in the β form is destabilized by 10–14 kJ mol^?1, depending on the calculation method. However, experimental evidence suggests that the β polymorph is the most stable crystalline phase at room temperature. This is attributed to the relative planarity of this structure, which allows more and stronger intermolecular interactions, that is, more energetically effective packing. Calculated electronic‐absorption maxima were in agreement with experimental spectra.