Shridhar H. Thorat

An Ultrahydrophobic Fluorous Metal–Organic Framework Derived Recyclable Composite as a Promising Platform to Tackle Marine Oil Spills

Derived from a strategically chosen hexafluorinated dicarboxylate linker aimed at the designed synthesis of a superhydrophobic metal-organic framework (MOF), the fluorine-rich nanospace of a water-stable MOF (UHMOF-100) exhibits excellent water-repellent features. It registered the highest water contact angle (≈176°) in the MOF domain, marking the first example of an ultrahydrophobic MOF. Various experimental and theoretical studies reinforce its distinctive water-repellent characteristics, and the conjugation of superoleophilicity and unparalleled hydrophobicity of a MOF material has been coherently exploited to achieve real-time oil/water separation in recyclable membrane form, with significant absorption capacity performance. This is also the first report of an oil/water separating fluorinated ultrahydrophobic MOF-based membrane material, with potential promise for tackling marine oil spillages.

Cu-Catalyzed iminative hydroolefination of unactivated alkynes en route to 4-imino-tetrahydropyridines and 4-aminopyridines

A general method for synthesizing 4-imino tetrahydropyridine derivatives is achieved, from readily available β-enaminones and sulfonyl azides, which comprises a sequential copper catalyzed ketenimine formation and its hitherto inaccessible intramolecular hydrovinylation. The products are shown as ready precursors for highly valuable 4-sulfonamidopyridine derivatives via DDQ mediated oxidation.

Drug-Drug Molecular Salt Hydrate of an Anticancer Drug Gefitinib and a Loop Diuretic Drug Furosemide: An Alternative for Multidrug Treatment

A 1:1 monohydrate salt containing gefitinib, an orally administrated chemotherapy treatment for lung and breast cancers and furosemide, a loop diuretic drug, commonly used in the treatment of hypertension and edema, has been prepared. The molecular salt crystallized in triclinic P-1 space group. The C-O bond lengths (~1.26 Å) in the COOH group show that proton transfer has occurred from furosemide to morpholine moiety of the gefitinib suggesting cocrystal to be ionic. The morpholine moiety of the gefitinib showed significant conformational change because of its involvement in conformation dictating the strong N-H···O hydrogen bonding interaction. The strong hydrogen bonding interaction between gefitinib and furosemide places their benzene rings in stacking mode to facilitate the generation of π-stack dimers. The neighboring dimers are bridged to each other via water molecule through N-H···O, C-H···O, O-H···N, and O-H···O interactions. The remarkable stability of the salt hydrate could be attributed to the strong hydrogen bonding interactions in the crystal structure. Interestingly, release of water from the lattice at 140°C produced new anhydrous salt that has better solubility and dissolution rate than salt hydrate. The drug-drug molecular salt may have some bearing on the treatment of patient suffering from anticancer and hypertension.

Capturing a novel metastable polymorph of the anticancer drug gefitinib

Gefitinib, a life-extending anticancer drug, exhibits solvent-mediated conformational polymorphism to yield stable (form I) and novel metastable (form II) polymorphs. Crystal structure analysis revealed 3D isostructurality in the molecular organization of the polymorphs, and the metastable polymorph undergoes a crystal-to-crystal thermal phase transition to the stable polymorph.

A novel one-pot multi-component synthesis of 3,3’-disubstituted oxindole and spirooxindole scaffolds via Sn-catalyzed C(sp3)–H functionalization of azaarenes by sequential Knoevenagel–Michael-cyclization reaction

Sn-catalyzed C(sp3)–H bond functionalization of 2-methyl azaarenes/2-(azaaryl)methanes has been achieved for the first time in a one-pot multi-component reaction with isatin and active methylene compounds via tandem sequential Knoevenagel–Michael-intramolecular C–N cyclization. This strategy provides new cost-effective access to potent and biologically/medicinally important spirooxindoles/3,3′-disubstituted 2-oxindoles in good to excellent yields.

The impact of modular substitution on crystal packing: the tale of two ureas

A small library of 13 (3a–m) compounds with modular positioning of iodide and urea/thiourea groups was synthesized in excellent yields in a single step synthetic protocol. The existence of the anticipated (thio)urea derivatives was unambiguously established using a combination of 1–2D NMR spectroscopy, ESI-MS and single crystal X-ray diffraction studies. These (thio)urea compounds were classified into four classes as follows: a) mono-substituted urea, b) di-substituted urea, c) di-substituted thiourea and d) electronically tailored di-substituted thiourea. The changes in molecular conformation and crystal packing due to the change in the relative positioning of the iodo group at the phenyl ring attached to one of the N atoms and different substituents at other N atoms in urea and thiourea derivatives have been discussed. The urea derivatives, in general, display the chain association through one-dimensional three-centered N–H⋯O hydrogen bonding interactions due to the trans–trans orientation of both NH protons with respect to the carbonyl group, whereas the thiourea compounds exhibit a centrosymmetric dimeric assembly via the complementary N–H⋯S interactions because of the trans–cis arrangement of the NH protons leading to either a helical or a sheet pattern. The presence of a nitro group at the para position of the thiourea derivative leads to trans–trans arrangement of both NH protons with respect to the thiocarbonyl groups, thus yielding a chain assembly through one-dimensional three-centered N–H⋯S interactions similar to urea derivatives. Associations of these chains or sheets in urea/thiourea derivatives through halogen bonding interactions (hal⋯hal, hal⋯π, hal⋯S etc.) generate a 2D assembly.

X-ray crystal structures and anti-breast cancer property of 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acids

Diastereomeric ‘2RS,4R’-2-arylthiazolidine-4-carboxylic acids (ATCAs) were synthesized and their resolution to chiraly pure N-BOC derivatives was attempted by column chromatography. The absolute stereochemistry of the resolved compounds was ascertained by X-ray single crystal structures. Further application of the synthesized compounds was studied for their in vitro anti-breast cancer activity against MCF7 cell line using DOX as a standard by MTT assay method. Cell morphology analysis was carried out by fluorescence microscopy. The compounds containing ‘2S’ absolute configuration in thiazolidine ring and presence of 2-NO2, 2,6-Cl groups on ‘2R’-aryl substituent showed significant anti-breast cancer activity where some of the compounds were found to be more active than DOX in terms of induced apoptosis mode of MCF7 cell death.

Crystal structures of the pyrazinamide-p-aminobenzoic acid (1/1) cocrystal and the transamidation reaction product 4-(pyrazine-2-carboxamido)benzoic acid in the molten state.

The synthesis of pharmaceutical cocrystals is a strategy to enhance the performance of active pharmaceutical ingredients (APIs) without affecting their therapeutic efficiency. The 1:1 pharmaceutical cocrystal of the antituberculosis drug pyrazinamide (PZA) and the cocrystal former p-aminobenzoic acid (p-ABA), C7H7NO2·C5H5N3O, (1), was synthesized successfully and characterized by relevant solid-state characterization methods. The cocrystal crystallizes in the monoclinic space group P2₁/n containing one molecule of each component. Both molecules associate via intermolecular O-H···O and N-H···O hydrogen bonds [O···O = 2.6102 (15) Å and O-H···O = 168.3 (19)°; N···O = 2.9259 (18) Å and N-H···O = 167.7 (16)°] to generate a dimeric acid-amide synthon. Neighbouring dimers are linked centrosymmetrically through N-H···O interactions [N···O = 3.1201 (18) Å and N-H···O = 136.9 (14)°] to form a tetrameric assembly supplemented by C-H···N interactions [C···N = 3.5277 (19) Å and C-H···N = 147°]. Linking of these tetrameric assemblies through N-H···O [N···O = 3.3026 (19) Å and N-H···O = 143.1 (17)°], N-H···N [N···N = 3.221 (2) Å and N-H···N = 177.9 (17)°] and C-H···O [C···O = 3.5354 (18) Å and C-H···O = 152°] interactions creates the two-dimensional packing. Recrystallization of the cocrystals from the molten state revealed the formation of 4-(pyrazine-2-carboxamido)benzoic acid, C12H9N3O3, (2), through a transamidation reaction between PZA and p-ABA. Carboxamide (2) crystallizes in the triclinic space group P1̅ with one molecule in the asymmetric unit. Molecules of (2) form a centrosymmetric dimeric homosynthon through an acid-acid O-H···O hydrogen bond [O···O = 2.666 (3) Å and O-H···O = 178 (4)°]. Neighbouring assemblies are connected centrosymmetrically via a C-H···N interaction [C···N = 3.365 (3) Å and C-H···N = 142°] engaging the pyrazine groups to generate a linear chain. Adjacent chains are connected loosely via C-H···O interactions [C···O = 3.212 (3) Å and C-H···O = 149°] to generate a two-dimensional sheet structure. Closely associated two-dimensional sheets in both compounds are stacked via aromatic π-stacking interactions engaging the pyrazine and benzene rings to create a three-dimensional multi-stack structure.

Co-crystals/salts of an anticancer drug gefitinib with dicarboxylic acids

Constant and consistent attempt to develop cocrystals/salts of an active pharmaceutical ingredient (API) with suitable coformer is gaining widespread research interest in contemporary areas. This is basically because cocrystals/salts of APIs show great promise in improving its pharmaceutically relevant properties such as solubility, bioavailability, compressibility, stability, hygroscopicity, crystallinity, etc. without altering their therapeutic efficiency. This has prompted pharmaceutical companies to engage in developmental aspects of cocrystals that not only include physicochemical characterization, but also its scale up, processing and formulations of these novel materials. We are interested in improving the solubility of anticancer drug, gefitinib (Iressa). It is orally administrated chemotherapy treatment for lung and breast cancers. However, it suffers from poor aqueous solubility and hence its bioavailability is poor. Gefitinib was screened for polymorphism [1] and cocrystals/salts synthesis. Interestingly, it displayed polymorphism and also formed several cocrystals/salts with numerous dicarboxylic acids. Although the newly generated polymorph showed solubility similar to the marketed form owing to their isostructurality, the cocrystals/salts showed a significant increase in the solubility of gefitinib. The cocrystals/salts forming ability of gefitinib with respect to its different hydrogen bond forming groups, tunable conformation flexibility offered by morpholine moiety that accommodates various cocrystal formers of different sizes and shapes made gefitinib an excellent candidate for cocrystals/salts preparation.[2]

CCDC 1434995: Experimental Crystal Structure Determination

Related Article: Soumya Mukherjee, Ankit M. Kansara, Debasis Saha, Rajesh Gonnade, Dinesh Mullangi, Biplab Manna, Aamod V. Desai, Shridhar H. Thorat, Puyam S. Singh, Arnab Mukherjee, Sujit K. Ghosh|2016|Chem.-Eur.J.|22|10937|doi:10.1002/chem.201601724