Fluoride Anions: Unexploited but Effective Halogen Bond Acceptors.

Due to their high electron density, fluoride anions can be considered the most effective halogen bond (HaB) acceptors among the halides. However, under common experimental conditions, F- uncommonly acts as HaB acceptor, expectedly as it is present in hydrated form. Herein we report that under specific crystallization conditions a hydrogen bond-free F- functioning as donor of electron density can be obtained, with the formed HaBs constituting the driving force of the observed crystal packings. Computations confirm the strength of these HaBs compared to analogous interactions involving other halides.

Interplay of Halogen and Hydrogen Bonding through Co-Crystallization in Pharmacologically Active Dihydropyrimidines: Insights from Crystal Structure and Energy Framework.

A solvent-assisted grinding method has been used to prepare co-crystals in substituted dihydropyrimidines (DHPM) that constitutes pharmacologically active compounds. These were characterized using FT-IR, PXRD, and single-crystal X-ray diffraction. In order to explore the possibility of formation of halogen (XB) and hydrogen bonding (HB) synthons in the solid state, co-crystallization attempts of differently substituted DHPM molecules, containing nitro, hydoxy, and chloro substituents, with different co-formers, such as 1,4-diiodo tetrafluorobenzene (1,4 DITFB) and 3-nitrobenzoic acid (3 NBA) were performed. The XB co-crystals (C2aXB, C2bXB, and C2cXB) prefer the formation of C-I⋅⋅⋅O/C-I⋅⋅⋅S XB synthon, whereas the HB co-crystal (C2dHB) is stabilized by N-H⋅⋅⋅O H-bond formation. Hirshfeld surface analysis revealed that the percentage contribution of intermolecular interactions for XB co-crystals prefer equal contribution of XB synthon along with HB synthon. Furthermore, the interaction energy was analyzed using energy frameworks, which suggests that their stability, a combination of electrostatics and dispersion, is enhanced through XB/HB in comparison to the parent DHPMs.

Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme.

A series of 1,2,3-trisubstituted indolizines (2a-2f, 3a-3d, and 4a-4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b-2d, 3a-3d, and 4a-4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a-4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16-64 µg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.

Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives.

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a-e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, ß = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.

Antidiabetic Activity of Dihydropyrimidine Scaffolds and Structural Insight by Single Crystal X-ray Studies.

BACKGROUND: This research project is designed to identify the anti-diabetic effects of the newly synthesized compounds to conclude the perspective of consuming one or more of these new synthetic compounds for diabetes management. INTRODUCTION: A series of dihydropyrimidine (DHPM) derivative bearing electron releasing and electron-withdrawing substituent's on phenyl ring (a-j) were synthesized and screened for antihyperglycemic( anti-diabetic) activity on streptozotocin (STZ) induced diabetic rat model. The newly synthesized compounds were characterized by using FT-IR, melting point, 1H and 13C NMR analysis. The crystal structure and supramolecular features were analyzed through single-crystal X-ray study. Anti-diabetic activity testing of newly prepared DHPM scaffolds was mainly based on their relative substituent on the phenyl ring along with urea and thiourea. Among the synthesized DHPM scaffold, the test compound c having chlorine group on phenyl ring at the ortho position to the hydropyrimidine ring with urea and methyl acetoacetate derivative shows moderate lowering of glucose level. However, the title compounds methyl 4-(4-hydroxy-3-methoxyphenyl)- 6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(g) and ethyl 4-(3-ethoxy-4- hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(h) having methoxy and ethoxy substituents on phenyl ring show significant hypoglycemic activity compared to the remaining compounds from the Scheme 1. METHODS: The experimental rat models for the study were divided into 13 groups (n = 10); group 1 animals were treated with 0.5% CMC (0.5mL) (vehicle); group 2 were considered the streptozotocin (STZ)/nicotinamide diabetic control group (DC) and untreated, group 3 diabetic animals were administered with gliclazide 50 mg/kg and act as a reference drug group. The remaining groups of the diabetic animals were administered with the newly synthesized dihydropyrimidine compounds in a single dose of 50 mg/kg orally using the oral gavage, daily for 7 days continuously. The blood glucose level was measured before and 72 hrs after nicotinamide-STZ injection, for confirmation of hyperglycemia and type 2 diabetes development. RESULTS: Blood glucose levels were significantly (p<0.05) reduced after treatment with these derivatives. The mean percentage reduction for gliclazide was 50%, while that of synthesized compounds were approximately 36%. CONCLUSION: Our result suggests that the synthesized new DHPM derivative containing alkoxy group on the phenyl ring shows a significant lowering of glucose level compared to other derivatives.

Crystal structure of a 1:1 cocrystal of nicotinamide with 2-chloro-5-nitro-benzoic acid.

In the title 1:1 cocrystal, C7H4ClNO4·C6H6N2O, nicotinamide (NIC) and 2-chloro-5-nitro-benzoic acid (CNBA) cocrystallize with one mol-ecule each of NIC and CNBA in the asymmetric unit. In this structure, CNBA and NIC form hydrogen bonds through O-H⋯N, N-H⋯O and C-H⋯O inter-actions along with N-H⋯O dimer hydrogen bonds of NIC. Further additional weak π-π inter-actions stabilize the mol-ecular assembly of this cocrystal.

Novel Series of Methyl 3-(Substituted Benzoyl)-7-Substituted-2-Phenylindolizine-1-Carboxylates as Promising Anti-Inflammatory Agents: Molecular Modeling Studies.

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 M, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents.

Design, synthesis, and structural elucidation of novel NmeNANAS inhibitors for the treatment of meningococcal infection.

Neisseria meningitidis is the primary cause of bacterial meningitis in many parts of the world, with considerable mortality rates among neonates and adults. In Saudi Arabia, serious outbreaks of N. meningitidis affecting several hundreds of pilgrims attending Hajj in Makkah were recorded in the 2000-2001 season. Evidence shows increased rates of bacterial resistance to penicillin and other antimicrobial agents that are used in the treatment of the meningococcal disease. The host's immune system becomes unable to recognize the polysialic acid capsule of the resistant N. meningitidis that mimics the mammalian cell surface. The biosynthetic pathways of sialic acid (i.e., N-acetylneuraminic acid [NANA]) in bacteria, however, are somewhat different from those in mammals. The largest obstacle facing previously identified inhibitors of NANA synthase (NANAS) in N. meningitidis is that these inhibitors feature undesired chemical and pharmacological characteristics. To better comprehend the binding mechanism underlying these inhibitors at the catalytic site of NANAS, we performed molecular modeling studies to uncover essential structural aspects for the ultimate recognition at the catalytic site required for optimal inhibitory activity. Applying two virtual screening candidate molecules and one designed molecule showed promising structural scaffolds. Here, we report ethyl 3-benzoyl-2,7-dimethyl indolizine-1-carboxylate (INLZ) as a novel molecule with high energetic fitness scores at the catalytic site of the NmeNANAS enzyme. INLZ represents a promising scaffold for NmeNANAS enzyme inhibitors, with new prospects for further structural development and activity optimization.

Molecular Bases for Anesthetic Agents: Halothane as a Halogen- and Hydrogen-Bond Donor.

Although instrumental for optimizing their pharmacological activity, a molecular understanding of the preferential interactions given by volatile anesthetics is quite poor. This paper confirms the ability of halothane to work as a hydrogen-bond (HB) donor and gives the first experimental proof that halothane also works as a halogen-bond (HaB) donor in the solid state and in solution. A halothane/hexamethylphosphortriamide co-crystal is described and its single-crystal X-ray structure shows short HaBs between bromine, or chlorine, and the phosphoryl oxygen. New UV/Vis absorption bands appear upon addition of diazabicyclooctane and tetra(n-butyl)ammonium iodide to halothane solutions, indicating that nitrogen atoms and anions may mediate the HaB-driven binding processes involving halothane as well. The ability of halothane to work as a bidentate/tridentate tecton by acting as a HaB and HB donor gives an atomic rationale for the eudismic ratio shown by this agent.

Benzothiazole analogs as potential anti-TB agents: computational input and molecular dynamics.

Biotin is very important for the survival of Mycobacterium tuberculosis. 7,8-Diamino pelargonic acid aminotransaminase (DAPA) is a transaminase enzyme involved in the biosynthesis of biotin. The benzothiazole title compounds were investigated for their in vitro anti-tubercular activity against two tubercular strains: H37Rv (ATCC 25,177) and MDR-MTB (multidrug-resistant M. tuberculosis, resistant to isoniazid, rifampicin, and ethambutol) by an agar incorporation method. The possible binding mode and predicted affinity were computed using a molecular docking study. Among the synthesized compounds in the series, the title compound {2-(benzo[d]thiazol-2-yl-methoxy)-5-fluorophenyl}-(4-chlorophenyl)-methanone was found to exhibit significant activity with minimum inhibitory concentrations of 1 µg/mL and 2 µg/mL against H37Rv and MDR-MTB, respectively; this compound showed the highest binding affinity (-24.75 kcal/mol) as well.

Crystal structure and Hirshfeld surface analysis of diethyl 2-[4-(4-fluoro-phen-yl)-2-methyl-4-oxobutan-2-yl]malonate.

The title compound, C18H23FO5, was synthesized by reacting diethyl malonate with 1-(4-fluoro-phen-yl)-3-methyl-but-2-en-1-one. The mol-ecule adopts a loose conformation stabilized by weak C-H⋯O and C-H⋯π inter-actions. In the crystal, the mol-ecules are joined by C-H⋯O contacts into infinite chains along the b-axis direction with a C(6) graph-set motif. Hirshfeld surface analysis and fingerprint plots demonstrate the predominance of H⋯H, O⋯H and F⋯H inter-molecular inter-actions in the crystal structure.

Structural analysis of 2-iodo-benzamide and 2-iodo-N-phenyl-benzamide.

The title compounds, 2-iodo-benzamide, C7H6INO (I), and 2-iodo-N-phenyl-benzamide, C13H10INO (II), were both synthesized from 2-iodo-benzoic acid. In the crystal structure of (I), N-H⋯O and hydrogen bonds form two sets of closed rings, generating dimers and tetra-mers. These combine with C-I⋯π(ring) halogen bonds to form sheets of mol-ecules in the bc plane. For (II), N-H⋯O hydrogen bonds form chains along the a-axis direction, while inversion-related C-I⋯π(ring) contacts supported by C-H⋯π(ring) interactions generate sheets of mol-ecules along the ab diagonal.

Crystal structure of 1-[3,5-bis-(tri-fluoro-meth-yl)phen-yl]-2-bromo-ethan-1-one.

The title compound, C10H5BrF6O, synthesized via continuous stirring of 3,5-bis-(tri-fluoro-meth-yl) aceto-phenone with bromine in an acidic medium and concentrated under reduced pressure, crystallizes with four mol-ecules in the unit cell (Z = 4) and one formula unit in the asymmetric unit. In the crystal, mol-ecules are linked in a head-to-tail fashion into dimers along the b-axis direction through weak C-H⋯Br and C-O⋯Csp2 inter-actions. C-H⋯O, C-F⋯π and F⋯F inter-actions are also observed.

Larvicidal study of tetrahydropyrimidine scaffolds against Anopheles arabiensis and structural insight by single crystal X-ray studies.

A series of methyl or ethyl 4-(substitutedphenyl/pyridyl)-6-methyl-2-oxo/thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (HPM) analogues 4a-g were synthesized and evaluated for larvicidal activity against Anopheles arabiensis. These newly synthesized compounds were characterized by spectral studies such as FT-IR, NMR (1 H and 13 C), LC-MS, and elemental analysis. The conformational features and supramolecular assembly of molecules 4a, 4b, and 4e were further analyzed from single crystal X-ray study. The larvicidal activity of these tetrahydropyrimidine pharmacophore series was analyzed based on their relative substituents. Among the synthesized HPM analogous from the series, compounds 4d and 4e both having electron withdrawing chlorine group on phenyl ring at the fourth position of the tetrahydropyrimidine pharmacophore exhibited the most promising larvicidal activity.

Crystal structure of methyl 4-(4-hy-droxy-phen-yl)-6-methyl-2-oxo-1,2,3,4-tetra-hydro-pyrimidine-5-carboxyl-ate monohydrate.

The title hydrate, C13H14N2O4·H2O, crystallizes with two formula units in the asymmetric unit (Z' = 2). The dihedral angles between the planes of the tetra-hydro-pyrimidine ring and the 4-hy-droxy-phenyl ring and ester group are 86.78 (4) and 6.81 (6)°, respectively, for one mol-ecule and 89.35 (4) and 3.02 (4)° for the other. In the crystal, the organic mol-ecules form a dimer, linked by a pair of N-H⋯O hydrogen bonds. The hydroxy groups of the organic mol-ecules donate O-H⋯O hydrogen bonds to water mol-ecules. Further, the hy-droxy group accepts N-H⋯O hydrogen bonds from amides whereas the water mol-ecules donate O-H⋯O hydrogen bonds to the both the amide and ester carbonyl groups. Other weak inter-actions, including C-H⋯O, C-H⋯π and π-π, further consolidate the packing, generating a three-dimensional network.

Synthesis, Polymorphism, and Insecticidal Activity of Methyl 4-(4-chlorophenyl)-8-iodo-2-methyl-6-oxo-1,6-dihydro-4H-pyrimido[2,1-b]quinazoline-3-Carboxylate Against Anopheles arabiensis Mosquito.

Mosquitoes are the major vectors of pathogens and parasites including those causing malaria, the most deadly vector-borne disease. The negative environmental effects of most synthetic compounds combined with widespread development of insecticide resistance encourage an interest in finding and developing alternative products against mosquitoes. In this study, pyrimido[2,1-b]quinazoline derivative DHPM3 has been synthesized by three-step chemical reaction and screened for larvicide, adulticide, and repellent properties against Anopheles arabiensis, one of the dominant vectors of malaria in Africa. The title compound emerged as potential larvicide agent for further research and development, because it exerted 100% mortality, while adulticide activity was considered moderate.

From metallic cluster-based ceramics to nematic hybrid liquid crystals: a double supramolecular approach.

We describe a new supramolecular approach combining host-guest and electrostatic interactions to design hybrid materials containing polyanionic bulky inorganic compounds and showing liquid crystalline properties.

Orthogonal halogen and hydrogen bonds involving a peptide bond model†Electronic supplementary information (ESI) available: Experimental part, DSC, IR spectroscopic and crystallographic data. CCDC 899779-899785. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ce01514bClick here for additional data file.Click here for additional data file.

The peptide bond model N-methylacetamide self-assembles with a range of dihalotetrafluorobenzenes forming co-crystals that all show the occurrence of orthogonal hydrogen and halogen bonds.

{2-[(1,3-Benzo-thia-zol-2-yl)meth-oxy]-5-fluoro-phen-yl}(4-chloro-phen-yl)methanone.

The asymmetric unit of the title compound, C21H13ClFNO2S, contains two independent mol-ecules with similar conformations. In the mol-ecules, the thia-zole ring is essentially planar [maximum atomic deviations = 0.014 (4) and 0.023 (5) Å] and is oriented with respect to the fluoro-phenyl ring and chloro-phenyl rings at 9.96 (18) and 70.39 (18)° in one mol-ecule and at 7.50 (18) and 68.43 (18)° in the other; the dihedral angles between the fluoro-phenyl and chloro-phenyl rings are 64.9 (2) and 64.6 (2)°, respectively. Inter-molecular C-H⋯O and C-H⋯F hydrogen bonds stabilize the three-dimensional supra-molecular architecture. Weak C-H⋯π and π-π inter-actions [centroid-centroid distance = 3.877 (3) Å] lead to a criss-cross mol-ecular packing along the c axis.

{2-[(1,3-Benzo-thia-zol-2-yl)meth-oxy]-5-chloro-phen-yl}(4-chloro-phen-yl)methan-one.

In the title compound, C21H13Cl2NO2S, the benzo-thia-zole ring makes dihedral angles of 0.94 (1) and 70.65 (5)° with the 4-chloro-phenyl-methanone unit and the 5-chloro-phenyl ring, respectively. The dihedral angle between the 4-chloro-phenyl-methanone unit and the 5-chloro-phenyl ring is 66.20 (5)°. The crystal structure consists of dimeric units generated by C-H⋯N hydrogen bonds, further linked by C-H⋯O and C-H⋯π inter-actions, leading to a three-dimensional network.