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Achieving the desired solubility and dissolution of active pharmaceutical ingredients (APIs) continues to be a big challenge in the pharmaceutical industry. In this regard, multicomponent solids of APIs such as salts and cocrystals have shown significant promise in resolving such solubility/dissolution issues. However, very little is known on how the APIs' solubility or dissolution is affected by the drug to coformer ratio in multicomponent solids. Betrixaban, is an anticoagulant drug approved in 2017 for the prevention of venous thromboembolism. During the alternate solid form development studies of the known betrixaban maleate, a rare multicomponent solid form, salt-cocrystal hydrate of betrixaban, was discovered and characterized thoroughly by spectroscopic, thermal, and X-ray crystallographic methods. Significantly, the new betrixaban maleate maleic acid hydrate (1:1:2:1) form has shown lower melting point (80 °C) as compared to its parent salt (197.5 °C). From such a large melting difference (117 °C) between the salt and salt-cocrystal hydrate of API, we anticipated substantially better solubility for the salt-cocrystal hydrate (low enthalpy). Furthermore, the predicted solubility also supported our anticipation. However, the powder dissolution tests at different pH conditions provided contrary results, that is, the salt-cocrystal hydrate showed 10 times lower solubility as compared to its salt. A detailed investigation, considering all the potential factors, revealed that "common-ion effect" could be a critical factor for the low solubility of the salt-cocrystal hydrate in which the API to coformer ratio is 1:3. To the best of our knowledge, this is the first case study on the solubility of pharmaceutical salt-cocrystal hydrates with an emphasis on "common-ion effect" or drug to coformer ratio.

Nanomechanics signifies a key tool to interpret the macroscopic mechanical properties of a porous solid in the context of molecular-level structure. However, establishing such a correlation has proved to be significantly challenging in porous covalent organic frameworks (COFs). Structural defects or packing faults within the porous matrix, poor understanding of the crystalline assembly, and surface roughness are critical factors that contribute to this difficulty. In this regard, we have fabricated two distinct types of COF thin films by controlling the internal order and self-assembly of the same building blocks. Interestingly, the defect density and the nature of supramolecular interactions played a significant role in determining the corresponding thin films' stress-strain behavior. Thin films assembled from nanofibers (∼1-2 μm) underwent large deformation on the application of small external stress (Tp-Azo

Insights into structure–mechanical property correlations in molecular and multicomponent crystals have recently attracted significant attention owing to their practical applications in the pharmace...

Abiraterone acetate (ABI) is a BCS class IV (low solubility and low permeability) drug, and it was approved by the US FDA with brand name Zytiga in April 2011 for patients suffering from metastatic...

We report the solid-state structural properties and phase transition behavior of 1,4-dibromo-2,3,5,6-tetramethylbenzene, demonstrating that this material undergoes an order–disorder phase transition below ambient temperature (at ca. 154 K on cooling and ca. 160 K on heating). In both the high-temperature and low-temperature phases, the crystal structure is based on π-stacking of the molecules. In the crystal structure of the high-temperature phase, the bromine occupancy in each substituent site is ca. 1/3 and the methyl group occupancy in each substituent site is ca. 2/3, consistent with statistical orientational disorder of the molecule between six distinct orientations. Natural-abundance solid-state 2H NMR spectroscopy confirms that, at ambient temperature, this disorder is dynamic via rapid molecular reorientation about an axis perpendicular to the aromatic ring. In the low-temperature phase, the bromine and methyl substituents occupy preferred sites within the crystal structure, with the distribution of site occupancies becoming progressively more ordered on decreasing temperature.

Distinct macroscopic mechanical responses of the three crystals of naphthalene diimide derivatives, 1Me, 1Et, and 1nPr, studied here are very intriguing because their molecular structures are very similar, with the difference only in the alkyl chain length. Among the three crystals examined, 1Me shows highly plastic bending nature, 1Et shows elastic flexibility, and 1nPr is brittle. A detailed investigation by nanoindentation and molecular dynamics (MD) simulations allowed us to correlate their distinct mechanical responses with the way the weak interactions pack in crystal structures. The elastic modulus (E) of 1Me is nearly an order of magnitude lower than that of 1Et, whereas hardness (H) is less than half. The low values of E and H of 1Me indicate that these crystals are highly compliant and offer a low resistance to plastic flow. As the knowledge of hardness and elastic modulus of molecular crystals alone is insufficient to capture their macroscopic mechanical deformation nature, that is, elastic, brittle, or plastic, we have employed three-point bending tests using the nanoindentation technique. This allowed a quantitative evaluation of flexibility of the three mechanically distinct semiconducting molecular crystals, which is important for designing larger-scale applications; these were complemented with detailed MD simulations. The elastic 1Et crystals showed remarkable flexibility even after 1000 cycles. The results emphasize that the alkyl side chains in functional organic crystals may be exploited for tuning their self-assembly as well as their mechanical properties. Hence, the study has broad implications, for example, in crystal engineering of various flexible, ordered molecular materials. C.M.R. acknowledges the financial support from the DST (DST/SJF/CSA-02/2014−15). R.D. and G.R.K. thank the IISER Kolkata for fellowship and instrumental facilities. K.B.R. thanks the DST-SERB, India, for the award of National Postdoctoral Fellowship (PDF/2015/000953). M.J.B. and C.T.C. acknowledge the support from ONR (N000141612333) and DOD-MURI (grant no. FA9550-15- 1-0514).

Brexpiprazole (BREX) is a well known drug used in the treatment of atypical psychotic disorder. BREX is known to exhibit photo-instability on granulation with the most commonly used binder, polyvinylpyrrolidone (PVP), in wet granulation. The present study reports a cocrystal of BREX with catechol (CAT), its structure elucidation using single crystal X-ray diffraction and its processability. The brexpiprazole–catechol (BRC) cocrystal crystallizes in the P21/c space group. Structural analysis of BRC shows R22(8) between BREX and CAT through weak C–H⋯O and strong O–H⋯O hydrogen bond interactions. BREX is marketed in tablet dosage form. The compatibility of the generated cocrystal in the presence of several excipients was evaluated using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The cocrystal remained stable, with no signs of incompatibility during the excipient compatibility study. Additionally, the cocrystal and plain BREX granulated with PVP as a binder and the chemical stability of the granules were investigated. Plain BREX showed oxidative degradation and formation of N-oxide degradation products under stability conditions within 7 days. More importantly, the BRC cocrystal displayed superior stability against stability conditions because the reactive site in the piperazine ring of the BREX moiety was blocked in the BRC cocrystal due to the hydrogen bond between the drug and co-former.

The dark-orange monomer single crystals of 1,1′-dioxo-1H-2,2′-biindene-3,3′-diyldidodecanoate (BIT-dodeca2) convert to a transparent single-crystalline polymer (PBIT-dodeca2) material via a single-...

The solids salinazide (Slz) and 3-chloro-2-nitrobenzoic acid (CNB) are thermosalient (TS) in nature in their single component forms; upon cocrystallization with pentafluorobenzoic acid (PNB) and 4,4′-bipyridine (BPY), respectively, they produced a salt (Slz-PFB) and a cocrystal, CNB-BPY, which are also TS in nature. A detailed structural analysis of all the forms in question is carried out to verify if a solid that shows TS behavior in its single component form can be used as a TS template to generate new TS multicomponent solid forms. The study is significant as the multicomponent approach may allow the generation of a library of new TS forms, for instance, to alter the response time, temperature, etc. This may also allow imparting an additional functionality (e.g., mechanochromic luminescence, conductivity, chemical reactivity, etc.) to the new solids upon appropriate selection of coformer(s).

Multidrug solids have potential to efficiently treat and control a plethora of medical conditions. With the objective of discovering multidrug forms, three new multidrug salts and a salt hydrate of an antibacterial drug, norfloxacin (BCS class IV drug) with four non-steroidal anti-inflammatory drugs (NSAIDs, BCS class II drugs), diclofenac (NOR–DIC), diflunisal (NOR–DIF), mefenamic acid (NOR–MEF) and indomethacin (NOR–IND–H2O), were prepared by liquid-assisted grinding. Single crystal X-ray diffraction (SCXRD) reveals that proton transfer from the carboxylic acid of the NSAIDs to the piperazinyl group of norfloxacin occurs in all the salts to form a robust tetrameric R44 (12) ring piperazine–carboxylate synthon by N+–H⋯O− bonding. Studies on the equilibrium solubility in different biological pH buffer solutions and membrane permeability have been carried out and a comparison is made with those of the parent drugs. A significant enhancement of norfloxacin solubility was observed for the pH 7.4 buffer solution in all the binary systems with the exception of the NOR–MEF salt. Also, a cumulative amount of NOR–DIF and NOR–IND–H2O binary systems show remarkable improvement in diffusion behavior compared to that of the individual pure drugs. Thus, the increasing physicochemical properties through the combined effect of improved solubility and permeability leads to the enhancement of bioavailability, which has implications that overcome the formulation-related problems of APIs.

Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform –infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P21/n, P21/c and P21/n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs.

Controlling mechanical properties of ordered organic materials remains a formidable challenge, despite their great potential for high performance mechanical actuators, transistors, solar cells, photonics, and bioelectronics. Here we demonstrate a crystal engineering approach to design mechanically reconfigurable, plastically flexible single crystals (of about 10) of three unrelated types of compounds by introducing active slip planes in structures via different noninterfering supramolecular weak interactions, namely van der Waals (vdW), π-stacking, and hydrogen bonding groups. Spherical hydrophobic groups, which assemble via shape complementarity (shape synthons), reliably form low energy slip planes, thus facilitating an impressive mechanical flexibility, which allowed molding the crystals into alphabetical characters to spell out "o r g a n i c c r y s t a l". The study, which reports the preparation of a series of exotic plastic crystals by design for the first time, demonstrates the potential of soft interactions for tuning the mechanical behavior of ordered molecular materials, including those from π-conjugated systems.

Multidrug solids have a potential use to efficiently treat and control a superfluity of medical conditions. To address the current drawbacks of drug development in R&D, it was targeted to achieve new pharmaceutical solid forms of fenamic acids having improved solubility and thermal stability. Subsequently, five new multicomponent solids consisting of three salt hydrates of trimethoprim (TMP) with mefenamic acid (TMP-MFA-H2O), tolfenamic acid (TMP-TFA-H2O) and flufenamic acid (TMP-FFA-H2O), and two cocrystals of sulfamethazine (SFZ) with flufenamic acid (SFZ-FFA) and niflumic acid (SFZ-NFA) were prepared by liquid assisted grinding. Looking at the structures of active pharmaceutical ingredient (API) molecules, it was quite expected that a wide range of supramolecular synthons would lead to co-crystallization. New forms were characterized thoroughly by various solid-state techniques, including single crystal X-ray diffraction (SCXRD), which provided details of hydrogen bonding, molecular packing and interactions between drug and coformer. Kinetic solubility at pH 7.4 buffer study has been carried out and a comparison is made with respect to the parent drugs. A significant enhancement of NSAIDs solubility was observed in all salt hydrate systems of TMP. Thus with increasing physicochemical properties such as improved solubility further leads to the enhancement of bioavailability, which has implications to overcoming the formulation related problems of active pharmaceutical ingredients (APIs).

Tuning mechanical performance of molecular materials is currently attractive owing to their practical applications in pharmaceutical, food, and fine chemical industries and optoelectronics. Here we employed a crystal engineering approach to transform four food flavouring agents, vanillin isomers, from brittle to soft solids by forming co-crystals with 6-chloro-2,4-dinitroaniline (cda). The series includes vanillin (van), ethylvanillin (evan), iso-vanillin (ivan), as well as a Schiff base of ortho-vanillin (ovan) with ethylene diamine (sb-ovan). All the co-crystals adopt flat two-dimensional (2D) layer packing, except the sb-ovan:cda, which adopts a corrugated layer packing with the presence of slip planes. The mechanical properties of the co-crystals were studied by (1) a qualitative method, (2) nanoindentation, and (3) powder compaction techniques, which allowed for successfully establishing the relationship among crystal structure, mechanical properties, and tablet tensile strength. The simple qualitati...

An undecairon(III) oxo-hydroxo-carboxylato bridged aggregate [Fe11(μ3-O)6(μ3-OH)6(μ-O2C-f)15] (1) has been synthesized and characterized by single crystal X-ray diffraction study. The anionic ligand N-(2-hydroxyethyl)-3-methoxysalicylaldimine (L) has been used as template to synthesize such high nuclearity complex. Interestingly, the ligand neither enters into the coordination sphere nor crystallizes with the iron cluster. Bond distance data indicate that all the iron atoms in 1 are high-spin Fe(III) in O-donor environment. 1 behaves as an effective catalyst towards oxidation of 3,5-di-tert-butylcatechol in different solvents, viz. methanol, dichloromethane and acetonitrile, to its corresponding quinone derivative in aerial oxygen. The reaction follows Michaelis–Menten enzymatic reaction kinetics with turnover numbers (Kcat) 3.21 × 103, 1.23 × 103 and 1.11 × 103 h−1 in methanol, dichloromethane and acetonitrile, respectively.

A correlation study between gelling/non-gelling behaviour and the presence (or absence) of a one-dimensional (1D) hydrogen-bonded network in single crystal structures of three galactose derivatives (p-methoxyphenyl-β-D-galactopyranoside (1), p-methoxyphenyl-3,4-O-isopropylidene-β-D-galactopyranoside (2) and p-methoxyphenyl-6-O-benzoyl-3,4-O-isopropylidene-β-D-galactopyranoside (3)) is attempted. Structure–property correlation studies in the literature suggest that the presence of a 1D hydrogen-bonded network promotes efficient gelation in hydrogen-bond-based gelators. Unexpectedly, saccharide 1 having a 2D hydrogen-bonded network (HBN) showed efficient gelation ability in various solvents, while saccharide 3 with a 1D HBN failed to show gelation. Failure of the latter could be due to unsuitable surface compatibility of self-assembled fibrillar networks (SAFiNs) and solvent molecules. On the other hand, saccharide 2 with a 2D HBN was found to be a non-gelator as expected. Importantly, saccharide 1, which is a simple, small and eco-friendly LMWG and can be easily prepared from cheaply available D-galactose, is an efficient gelator for 1,2-dichlorobenzene with a critical gelation concentration of only 0.25% w/v. FT-IR spectroscopy showed the involvement of intermolecular hydrogen bonding in the gelation process, and rheological experimental results confirmed its true gel behaviour. SEM and AFM studies revealed the fibrous entanglement of the molecules in the gel state.

The exceptional mechanical flexibility observed with certain organic crystals defies the common perception of single crystals as brittle objects. Here, we describe the morphostructural consequences of plastic deformation in crystals of hexachlorobenzene that can be bent mechanically at multiple locations to 360° with retention of macroscopic integrity. This extraordinary plasticity proceeds by segregation of the bent section into flexible layers that slide on top of each other, thereby generating domains with slightly different lattice orientations. Microscopic, spectroscopic and diffraction analyses of the bent crystal showed that the preservation of crystal integrity when stress is applied on the (001) face requires sliding of layers by breaking and re-formation of halogen-halogen interactions. Application of stress on the (100) face, in the direction where π···π interactions dominate the packing, leads to immediate crystal disintegration. Within a broader perspective, this study highlights the yet unrecognized extraordinary malleability of molecular crystals with strongly anisotropic supramolecular interactions.

One co-crystal and one salt of an antibacterial drug sulfathiazole with 4-aminobenzamide and 2,4-dinitrobenzoic acid have been synthesized. These new forms are characterized by single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). In solid state, sulfathiazole preferentially adopts the imidine tautomeric form.

Single crystal structures of two solid drug forms, namely tramadol hydrochloride and tramadol hydrochloride acetonitrile solvate, are reported. The crystal structure analysis reveals that the packing in the two forms is very similar and both are dominated by O–H···Cl−···H–N+ supramolecular synthons. The two forms have also been characterized by differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction and infrared spectroscopy. Layering crystallization method is shown to yield better quality single crystals of the two forms compared to the slow evaporation crystallization from single solvent. Crystallization of tramadol hydrochloride and its acetonitrile solvate from layering of hexane on top of solution, crystal structure analysis and their thermal behavior is investigated.

Two salt forms of a fluoroquinolone antibacterial drug, ciprofloxacin (CIP), with non-steroidal anti-inflammatory drugs, diflunisal (CIP/DIF) and indoprofen (CIP/INDP/H2O), were synthesized and characterized by PXRD, FTIR, DSC, TGA and HSM. Crystal structure determination allowed us to study the drug–drug interactions and the piperazine-based synthon (protonated piperazinecarboxylate) in the two forms, which is potentially useful for the crystal engineering of new salt forms of many piperazine-based drugs.

Succinylsulfathiazole (SST) is known to exist in seven different crystalline forms, namely two unsolvated polymorphic forms (SST-I, SST-II), a monohydrate (SST/H2O), dihydrate (SST/2H2O) and solvates of butanol (SST/But), pentanol (SST/Pnt) and dioxane (SST/Diox). Most of these forms have been characterised only by IR and PXRD, while the single crystal structures have been determined for SST/But, SST/Pnt, SST/H2O and SST/Diox solvates. Previous studies also noted a lack of reproducibility in preparation of these different forms. Here, we employed a fast evaporation (FE) crystallization method and identified two new solvates from acetone (SST/AcMe) and tetrahydrofuran (SST/THF), as well as determined the single crystal structures for SST-I, SST-II, SST/AcMe and SST/THF. This revealed that SST exclusively adopts the imidine tautomeric form in all its solid form structures, but never the amidine form. The succinyl group of SST shows a conformational flexibility and adopts either anti- or syn-geometry to facilitate hydrogen bonding in the different structures. The study also allowed us to rationalize the hydrogen bonding preferences of various functional groups in all the forms. Notably the neat grinding and liquid assisted grinding methods resulted in only SST/H2O from various solvents, while the FE method produced polymorphs or pseudopolymorphs from different solvents.

The synthesis, crystal structure and variable temperature magnetic measurements of a new dinuclear Fe(III) complex, [Fe2(μ1,3-O2Cfn)(OH2)(MeOH)Cl2L] (1) [fn = furan, L = N,N′-bis(salicyaldehydene)-1,3-diaminopropan-2-ol], is reported. From X-ray diffractometry, it is shown that each Fe(III) centre in 1 is in a distorted octahedral environment. A variable temperature magnetic study reveals strong antiferromagnetic behaviour of 1 with J = −22.2 ± 0.1 cm−1. Use of 1 as an alkene epoxidation catalyst towards (E)-stilbene and styrene with tert-butyl hydrogen peroxide (TBHP) and iodosylbenzene (PhIO) reveals that TBHP is the better oxidant in terms of the yield of the reaction.

Thiasalen podand 9 having S2N2 donor set has been synthesized by the condensation of 2-methylthiobenzaldehyde with ethylenediamine. The reaction of the thiasalen podand ligand with Pd(II) afforded two complexes depending on the reaction time. Shorter reaction time (5 min) afforded thioether complex 10; whereas with increase in reaction time (4 h) thioether-thiolate complex 11 was obtained via cleavage of one of the two S-C(Me) bonds of bis(methyl)thiasalen podand upon complexation. The reaction of 9 with Pt(II) afforded only thiolate-thioether complex 12 independent of the reaction time. The cleavage of both the S-C(Me) bonds of bis(methyl)thiasalen to afford bisthiolate complexes has never been observed. The structures of thiasalen podands and all three complexes have been determined by single crystal X-ray diffraction analysis. All three complexes possess a square planar geometry around the metal centres. Weak van der Waals interactions through C-H···F interactions are present in all three complexes leading to the formation of supramolecular synthons and the supramolecular structures are stabilized by aromatic π···π interactions, which leads to the formation of 3D pseudo-double helical network packing. Under similar conditions bis(methyl)salen did not form any complexes with Pd(II) and Pt(II).

A series of N2Se2 and N2Se2O2 acyclic Schiff base diselenides ( 3 – 9 ) have been synthesized by condensation of bis( o -formylphenyl) diselenide and amines (aniline, p -bromoaniline, benzylamine, ethanolamine, 1-aminopropanol, 2-aminophenol). The Schiff base diselenides were characterized by elemental analysis, ESI-MS, NMR ( 1 H, 13 C, 77 Se) spectroscopy and X-ray crystallography. During crystallization compound 6 afforded bis(phenyloxazoline) diselenide 9 via cyclization of Schiff base of ethanolamine. The supramolecular nature of these diselenides is studied by X-ray crystallographic structure analysis.

We show the preferential formation and scalability of two known polymorphs, I and II, of aspirin from acetone (at 50 °C) and dichloromethane (at 5 °C) solutions, respectively, and two known forms I (from water at 50 °C) and II (from methanol at 50 °C) of anthranilic acid with high purity by fast evaporation (FE) of solvent using rotary evaporation technique. The FE method also provided a means to identify a previously unknown form II of niflumic acid (NFA). The NFA form II, which is characterized by DSC, TGA, IR, and PXRD, could not be detected either by slow evaporation or liquid assisted grinding methods upon screening from a variety of solvents. The results demonstrate the efficiency and complementarity of the FE method to the existing techniques for selective preparation and scale up of API polymorphic forms.

A regioselective route to novel mono triazolyl substituted quinolines has been developed via copper-catalyzed azide–alkyne cycloaddition (CuAAC) of 2,4-diazidoquinoline with terminal alkynes in DMF. The reaction provided bis triazolyl substituted quinolines when performed in water in the presence of Et3N. A number of the compounds synthesized showed promising anti-proliferative properties when tested in vitro especially against breast cancer cells.

Two novel quinoline derivatives e.g. 2-(3-(hydroxymethyl)-7-methylquinolin-2-yl)phenol (1) and 2-(3-(hydroxymethyl)-6-methoxyquinolin-2-yl)phenol (2) were synthesized. These compounds were characterized by IR, 1H NMR and mass spectroscopy. Thermal analyses (DSC and TGA) and PXRD patterns were collected for the supporting data. Finally the crystal structures were solved by single crystal X-ray diffraction data and the structures were analyzed in terms of supramolecular interactions. Compound 1 consists of two symmetry independent molecules in the asymmetric unit. These two molecules are conformational isomers (A and B) and form different hydrogen bonding in the crystal structure. The Hirshfeld surfaces and associated 2D fingerprint plots were analyzed to differentiate the two conformers (A and B). Compound 2 form a helical structure with O–H⋯O and O–H⋯N hydrogen bond synthons along the c-axis.

A number of 2-(1 H -indol-3-yl)quinoline-3-carbonitrile derivatives were synthesized via AlCl 3 -mediated C–C bond forming reaction between 2-chloroquinoline-3-carbonitrile and various indoles. The methodology does not require any N-protection of the indoles employed and provided the corresponding products in good yields. The molecular structure of a representative compound was established unambiguously by single crystal X-ray diffraction and structural elaboration of a compound synthesized has been demonstrated. Many of these compounds synthesized showed PDE4 inhibitory properties in vitro. A brief structure–activity relationship studies within the series along with docking results of a representative compound (EC 50 ∼0.89 μM) is presented.

A direct and single-step method has been developed for the synthesis of mono and 2,3-disubstituted quinoxalines by using a AlCl3 induced (hetero)arylation of 2,3-dichloroquinoxaline. Both symmetrical and unsymmetrical 2,3-disubstituted quinoxalines can be prepared conveniently by using this method under appropriate reaction conditions. The reaction proceeds via C–C bond formation and can be utilized for the preparation of a variety of quinoxaline derivatives from readily available starting materials and reagents. The molecular structure of a representative compound was confirmed by single crystal X-ray diffraction study. Some of the compounds synthesized were tested for chorismate mutase inhibitory properties in vitro and one compound showed promising activity representing one of the few examples of chorismate mutase inhibition by a heteroarene based small molecule.

A new and one-pot synthesis of benzofuran fused N-heterocycles has been accomplished via AlCl3-mediated C–C followed by C–O bond formation between 2,3-dichloropyrazine or its derivatives and phenols. The methodology provided novel compounds as potential inhibitors of PDE4B. The single crystal X-ray data of a synthesized benzofuran derivative are presented. Scope of the methodology, in vitro pharmacological data of some of the synthesized compounds, along with docking study of an active compound are described.

An efficient and clean method has been developed for the synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones using Amberlyst-15 as a recyclable catalyst. A variety of dihydroquinazolinones were prepared from 2-aminobenzamide and aldehydes under mild conditions in excellent yields. Further structure elaboration of one compound and the crystal structure analysis and hydrogen bonding patterns of the two compounds prepared by using this methodology is presented.

Synthesis and single crystal X-ray diffraction studies of four transition metal complexes [Mn(L1)](ClO4)2 (1), [Cu(L1)](ClO4)2 (2), [Ni2(L2)(NCS)6][Ni(L1)] (3) and [Mn(bzpy)(NCS)2] (4) with neutral ligands [L1 = N-(1-pyridin-2-yl-phenylidene)-N′-[2-({2-[(1-pyridin-2-yl phenylidene)amino]ethyl}amino)ethyl]ethane-1,2diamine, L2 = N-(1-pyridin-2-yl-phenylidene)-N′-[2-({2-[(1-pyridin-2-ylphenylidene)amino]ethyl}piperazine-1yl)ethyl]amine, bzpy = 2-benzoylpyridine] are reported. The trinuclear nickel(II) complex 3 is made of a dinuclear anion and a mononuclear cation. Variable-temperature magnetic susceptibility and variable-field magnetisation studies performed on 3 suggest weak antiferromagnetic coupling (J = −0.7 cm−1) between the two metals of the dinuclear entity, but no magnetic interaction between the anionic and cationic counterparts.

Ten new co-crystals of an antibacterial drug sulfamethazine (SFZ) with various carboxylic acid and amide co-formers have been synthesized. These new forms are characterized by single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Crystal structures with 4-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DHB), 3,4-dichlorobenzoic acid (DCB), sorbic acid (SOR), fumaric acid (FUM), 1-hydroxy-2-naphthoic acid (1HNA), benzamide (BEN), picolinamide (PIC), 4-hydroxybenzamide (HBEN), and 3-hydroxy-2-naphthoic acid (3HNA) are determined. The SFZ molecule displays co-former assisted amidine to imidine tautomerism in the co-crystals in that the sulfonamide NH proton moves to one of the pyrimidine N atoms. In all the cases, the SFZ forms a robust hydrogen bonded synthon with a carboxylic acid (amidine(SFZ)···acid/imidine(SFZ)···acid) or amide (imidine(SFZ)···amide) group from the co-former. The SFZ molecule, in all the carboxylic a...

The nanoindentation technique has been employed to relate the mechanical properties of saccharin single crystals with their internal structure. Indentations were performed on (100) and (011) faces to assess the mechanical anisotropy. The load-displacement (P-h) curves indicate significant differences in the nature of the plastic deformation on the two faces. The P-h curves obtained on the (011) plane are smooth, reflecting homogeneous plasticity. However, displacement bursts (pop-ins) are observed in the P-h curves obtained on the (100) plane suggesting a discrete deformation mechanism. Marginal differences exist in the hardness and modulus on the two faces that may, in part, be rationalized, although one notes that saccharin has a largely three-dimensional close-packed structure. The structural origins of the fundamentally different deformation mechanisms on (100) and (011) are discussed in terms of the dimensionality of the hydrogen bonding networks. Down the (100) planes, the saccharin dimers are stacked and are stabilized by nonspecific van der Wants interactions mostly between aromatic rings. However, down the (011) planes, the molecules are stabilized by more directional and cross-linked C-H ... O hydrogen bonds. This anisotropy in crystal packing and interactions is reflected in the mechanical behavior on these faces. The displacements associated with the pop-ins were found to he integral multiples oldie molecule separation distances. Nanoindentation offers an opportunity to compare experimentally, and in a quantitative way, the various intermolecular interactions that fire present in a molecular crystal.

Bending of crystals of molecular solids occurs when the strength of intermolecular interactions in orthogonal directions is significantly different. We report here a survey of 60 molecular crystals and establish a causative correlation between bending and crystal packing. This group contains crystals with 4 and 8 A crystal axes and includes 1D, 2D, 3D, isostructural, polymorphic, stacked, interlocked, single, and multicomponent crystals and solvates. We found that 17 of these 60 crystals may be bent, whereas the rest are brittle and cannot be bent plastically. The bending crystals could be deformed into many shapes; sometimes, they could even be flattened upon themselves without breakage. A model for bending is proposed using the information obtained from X-ray diffraction, face indexing, and mechanical property measurements on both bending and non-bending (brittle) crystals. The bending and brittleness of these molecular crystals are discussed in comparison with the deformation behavior of metals. Molecu...

The title amide host 1 crystallizes in the wheel-and-axle framework via amide N–H⋯O dimer and includes several aromatic and aliphatic guest molecules in cavities of 40 A2 size between supramolecular axles. Bulky triphenylmethyl groups make it impossible for the second NH donor to engage in strong hydrogen bonding and this promotes a weak intermolecular N–H⋯π interaction in inclusion adducts of aromatic and hydrophobic guests (structure type 1, guest = xylenes, chloro/bromo-toluene). On the other hand, the N–H⋯π interaction is absent for guests with CO groups because of stronger N–H⋯Oguest hydrogen bonding (type 2, guest = EtOAc, MeNO2). Crystal structures of both types are virtually identical except for the rotation of CONH2 group that transforms the N–H⋯π interaction to the N–H⋯O hydrogen bond. In addition to controlling the occurrence of the weak N–H⋯π hydrogen bond through host⋯guest recognition, a third structure type with N–H⋯Ohost and N–H⋯π hydrogen bonds is present in the anisole adduct. Amide group conformations, strong and weak hydrogen bonds, and close packing of aromatic residues determine the three structure types of composition 1·(guest)0.5 in space group P. The CH2Cl2 solvate, 1·(CH2Cl2)1.5, has a different crystal packing in space group C2/c with guest molecules included in channels between amide dimers and also between Ph3C groups. The design and control of the weak N–H⋯π hydrogen bond are shown for the first time in a family of isomorphous crystal structures. Infrared spectroscopy and variable temperature X-ray diffraction are consistent with the hydrogen bond nature of the N–H⋯π interaction. Differential scanning calorimetry and thermal gravimetric analysis confirm the functional behavior of inclusion host 1 and show differences in the release of CH2Cl2 molecules from the two types of channels. Crystal latttice energies follow the order structure type 3 < type 2 < type 1 in the range of −90 to −76 kcal mol−1 per host molecule.

A rapid, versatile and one-pot Cu-mediated domino reaction has been developed for facile assembly of two six membered fused N-heterocyclic rings leading to novel small molecules as potential inhibitors of PDE4.

The title compound C15H18N4O2 (I), was prepared from the reaction of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide and 4-hydroxybenzaldehyde; and was analyzed by analytical data from 1H NMR, 13C NMR, IR and Mass spectra. The crystal structure was determined by single crystal X-ray diffraction. The molecules in the crystal structure form cyclic centrosymmetric supramolecular tetramer synthons [graph-set R 4 4 ( 12 ) ] through amide N–H⋯O(hydroxy) and hydroxy O–H⋯O(amide) hydrogen bonds to form perpendicular tapes.

With a view to find novel inhibitors of sirtuins, a series of indolo[2,3-b]indoles (IV) is prepared by a palladium-catalyzed intramolecular cyclization of iodides (III).

With a view to find novel inhibitors of phosphodiesterase-4, a variety of fused tetra- and pentacyclic heterocycles is prepared by Cu-mediated domino reaction of starting carboxylic esters with nitriles (36 examples).

The acetylation of indole (IIIe) in the presence of AlCl3 leads to desired 3-acetyl derivative (VII), whilst the analogous reaction of 2-tert-butylindoles (IIIa)—(IIId) is accompanied by an unexpected migration of the sulfonyl group.

Although weak interactions, such as C-H center dot center dot center dot O and pi-stacking, are generally considered to be insignificant, it is their reorganization that holds the key for many a solid-state phenomenon, such as phase transitions, plastic deformation, elastic flexibility, and mechanochromic luminescence in solid-state fluorophores. Despite this, the role of weak interactions in these dynamic phenomena is poorly understood. In this study, we investigate two co-crystal polymorphs of caffeine:4-chloro-3-nitrobenzoic acid, which have close structural similarity (2D layered structures), but surprisingly show distinct mechanical behavior. Form I is brittle, but shows shear-induced phase instability and, upon grinding, converts to Form II, which is soft and plastically shearable. This observation is in contrast to those reported in earlier studies on aspirin, wherein the metastable drug forms are softer and convert to stable and harder forms upon stressing To establish a molecular level understanding, have investigated the two co-crystal polymorphs I and II by single crystal X-ray diffraction, nanoindentation to quantify mechanical properties, and theoretical calculations. The lower hardness (from nanoindentation) and smooth potential surfaces (from theoretical studies) for shearing of layers in Form II allowed us to rationalize the role of stronger intralayer (sp(2))C-H center dot center dot center dot O and nonspecific interlayer pi-stacking interactions in the structure of II. Although the Form I also possesses the same type of interactions, its strength is clearly opposite, that is, weaker intralayer (sp(3))C-H center dot center dot center dot O and specific interlayer pi-stacking interactions. Hence, Form I is harder than Form IL Theoretical calculations and indentation on (111) of Form I suggested the low resistance of this face to mechanical stress; thus, Form I converts to II upon mechanical action. Hence, our approach demonstrates the usefulness of multiple techniques for establishing the role of weak noncovalent interactions in solid-state dynamic phenomena, such as stress induced phase transformation, and hence is important in the context of solid-state pharmaceutical chemistry and crystal engineering.

The crystal structure of the title compound, alternatively called 1,2,3-triiodo-5-(triphenylmethyl)benzene, C 25 H 17 I 3 , is analysed in terms of I...I and I...π interactions and the herring-bone T motif between phenyl groups. There are two molecules in the asymmetric unit, denoted A and B. Inversion-related A molecules are connected via an I...π interaction (3.641 A, to a C-C bond mid-point) to form an I...π dimer, and these dimers are connected through symmetry-independent B molecules via I...I [3.5571 (15) A] and I...π (3.561 A, to a C-C bond mid-point) interactions.

A rapid and direct access to N-aryl substituted fused triazinone derivatives is accomplished via Cu-mediated N-arylation.

Novel thieno[2,3-d]pyrimidines containing a cyclohexane ring fused with a six- or five-membered heterocyclic moiety along with a benzylic nitrile were designed as potential inhibitors of PDE4. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of a few key steps such as Gewald reaction, Dieckmann type cyclisation and Krapcho decarboxylation. This newly developed strategy involved construction of the thienopyrimidine ring followed by the cyclohexanone moiety and subsequently the fused heterocyclic ring. A number of thieno[2,3-d]pyrimidine based derivatives were synthesized using this method some of which showed promising PDE4B inhibitory properties. One of them was tested for PDE4D inhibition in vitro and dose dependent inhibition of TNF-α. A few selected molecules were docked into the PE4B protein the results of which showed good overall correlations to their observed PDE4B inhibitory properties in vitro. The crystal structure analysis of representative compounds along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.

A series of novel N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones were designed and synthesized as potential inhibitors of chorismate mutase. Synthesis of this class of compounds was carried out by using Cu-mediated C-N bond forming reaction between thieno[2,3-d]pyrimidin-4(3H)-ones and aryl boronic acids. The reaction can be performed in an open flask as the conversion was found to be not sensitive to the presence of air or atmospheric moisture. A range of compounds were prepared by using this method and single crystal X-ray diffraction study was performed using a representative compound. In vitro pharmacological data of some of the compounds synthesized along with dose response studies using active molecules are presented. In silico interactions of these molecules with chorismate mutase are also presented.

The AlCl3-mediated cyclocondensation of 2,3-dichloropyrazine derivatives with 2-naphthol or resorcinol monoalkyl ethers offers a direct synthesis of various polycyclic bis-fused furan derivatives.

Novel polysubstituted pyrroles have been designed and accessed via a one-pot multicomponent reaction followed by Pd-mediated C-C bond forming reactions. All the compounds synthesized were tested for their PDE4B inhibitory properties in vitro and two of them obtained via Heck reaction showed significant inhibition. The docking results suggested that these alkenyl derivatives containing ester moiety interact well with the PDE4B protein in silico where the ester carbonyl oxygen played a key role. The pyrrole framework presented here could be a new template for the identification of small molecule based novel inhibitors of PDE4. The single crystal X-ray data of a representative compound is presented.