Transition-Metal-Free Cyclization of Propargylic Alcohols with Aryne: Synthesis of 3‑Benzofuranyl-2-oxindole and 3‑Spirooxindole Benzofuran Derivatives

An unprecedented base-mediated cyclization of propargylic alcohols with aryne is reported, providing a novel method for the synthesis of 3-benzofuranyl-2-oxindole and 3-spirooxindole benzofuran scaffolds via a propargyl Claisen rearrangement/cycloaddition pathway. The nature of the substituent on acetylene group of propargylic alcohol influences the outcome of the reaction. The protocol offers a transition-metal-free and operationally simple methodology with broad substrate scope as a ready access to complex oxindole-linked heterocyclic compounds

Sequential C–N and C–O Bond Formation in a Single Pot: Synthesis of 2<i>H</i>-Benzo[<i>b</i>][1,4]oxazines from 2,5-Dihydroxybenzaldehyde and Amino acid Precursors

Functionalized β-aryl alanine ester derivatives were found to undergo rapid C–N and C–O bond formation with quinol carbonyl compounds to afford 2<i>H</i>-benzo[<i>b</i>][1,4]oxazines in good to excellent yields. This unprecedented finding reported herein offers a straightforward, highly efficient, and rapid method for the synthesis of 2<i>H</i>-benzo[<i>b</i>][1,4]oxazines

Sequential C–N and C–O Bond Formation in a Single Pot: Synthesis of 2<i>H</i>-Benzo[<i>b</i>][1,4]oxazines from 2,5-Dihydroxybenzaldehyde and Amino acid Precursors

Functionalized β-aryl alanine ester derivatives were found to undergo rapid C–N and C–O bond formation with quinol carbonyl compounds to afford 2<i>H</i>-benzo[<i>b</i>][1,4]oxazines in good to excellent yields. This unprecedented finding reported herein offers a straightforward, highly efficient, and rapid method for the synthesis of 2<i>H</i>-benzo[<i>b</i>][1,4]oxazines

Asymmetric Robinson Annulation of 3‑Indolinone-2-carboxylates with Cyclohexenone: Access to Chiral Bridged Tricyclic Hydrocarbazoles

A chiral bifuntional thiourea catalyzed diastereo- and enantioselective Michael addition followed by an intramolecular Aldol reaction of 3-indolinone-2-carboxylates with cyclohexenone has been accomplished using a chiral thiourea catalyst. It is a novel strategy for the construction of chiral bridged tricyclic hydrocarbazole derivatives bearing four contiguous stereocenters with excellent diastereo- and enantioselectivity

Cocrystal and Coamorphous Solid Forms of Enzalutamide with Saccharin: Structural Characterization and Dissolution Studies

Cocrystallization and coamorphization are similar yet independent approaches toward modifying various pharmaceutically relevant properties of modern drug compounds, in particular, solubility, dissolution rate, and the associated bioavailability. In this work, both strategies were applied to enzalutamide (Enz), a poorly soluble nonsteroidal antiandrogen drug, which led to the development of new multicomponent crystalline and amorphous solid forms of the drug with saccharin (Schr) in a 1:1 molar ratio. The structural analysis of the cocrystal formed by Enz and Schr revealed multiple intermolecular interactions between the components. Both Enz···Enz and Schr···Schr interactions were observed in the crystal packing. With the aid of N–H···O, C–H···O, C–H···N, and C–H···S hydrogen bonds, the molecules were aggregated into a three-dimensional hydrogen-bonded network. In the coamorphous composition, however, the components do not seem to involve in any strong intermolecular interactions and undergo recrystallization separately upon storage at room and elevated temperatures. The thermodynamic solubility of the cocrystal, evaluated using eutectic concentrations of the components, was found to be higher than that of the parent enzalutamide over an entire range of physiological pH values. The advantages and drawbacks of both formulation methods were analyzed and discussed, taking into account a tradeoff between physical stability and dissolution performance of the considered coamorphous composition and the cocrystal

I₂‑Catalyzed Oxidative N–S Bond Formation: Metal-Free Regiospecific Synthesis of N‑Fused and 3,4-Disubstituted 5‑Imino-1,2,4-thiadiazoles

A novel and expeditious approach for the synthesis of N-fused and 3,4-disubstituted 5-imino-1,2,4-thiadiazole derivatives has been achieved through the molecular iodine-catalyzed oxidative cyclization of 2-aminopyridine/amidine and isothiocyanate via N–S bond formation at ambient temperature. The present one-pot transition-metal-free protocol provides the facile and highly efficient regiospecific synthesis of various 1,2,4-thiadiazole derivatives in a scaled-up manner with good to excellent yields using inexpensive I₂ as a catalyst

Ionic, Neutral, and Hybrid Acid–Base Crystalline Adducts of Lamotrigine with Improved Pharmaceutical Performance

Lamotrigine (L) is a known drug in the treatment of epilepsy and bipolar disorder. Due to its unique structure and functionalities, L is able to form both salts and cocrystals. The present study reports ionic, neutral, and hybrid crystalline forms of L with improved material properties and modified drug release rates. Novel forms of L with cinnamic acid (CA), ferulic acid (FRA), salicylic acid (SAC), and vanillin (VN) were successfully prepared and characterized using single crystal XRD, SEM, FT–IR, DSC, TGA, and powder XRD. LCA and LVN crystallized in <i>P</i>2₁/<i>c</i> space group, whereas LSAC crystallized in <i>P</i>1̅ space group. Pseudo-quadruple hydrogen bond with R₄² (16) graph set notation were observed in all three crystal structures of L. The characteristic FT–IR stretching peaks at 3326.53, 3341.53, and 3340.65 cm^–1 corresponding to N⁺–H bond were observed in LCA, LFRA, and LSAC. Comparison of dissolution profiles using similarity factor (f2) analysis revealed that the dissolution profiles of LCA, LFRA, and LVN were significantly different from that of L. LVN exhibited improved dissolution rate compared to L and LCA revealed a sustained release profile. Both these properties are important in designing oral dosage forms for neuropathic pain and bipolar disorder therapy. Further, LCA can be used in the development of extended release drug delivery systems for treating epileptic disorders

Ionic, Neutral, and Hybrid Acid–Base Crystalline Adducts of Lamotrigine with Improved Pharmaceutical Performance

Lamotrigine (L) is a known drug in the treatment of epilepsy and bipolar disorder. Due to its unique structure and functionalities, L is able to form both salts and cocrystals. The present study reports ionic, neutral, and hybrid crystalline forms of L with improved material properties and modified drug release rates. Novel forms of L with cinnamic acid (CA), ferulic acid (FRA), salicylic acid (SAC), and vanillin (VN) were successfully prepared and characterized using single crystal XRD, SEM, FT–IR, DSC, TGA, and powder XRD. LCA and LVN crystallized in <i>P</i>2₁/<i>c</i> space group, whereas LSAC crystallized in <i>P</i>1̅ space group. Pseudo-quadruple hydrogen bond with R₄² (16) graph set notation were observed in all three crystal structures of L. The characteristic FT–IR stretching peaks at 3326.53, 3341.53, and 3340.65 cm^–1 corresponding to N⁺–H bond were observed in LCA, LFRA, and LSAC. Comparison of dissolution profiles using similarity factor (f2) analysis revealed that the dissolution profiles of LCA, LFRA, and LVN were significantly different from that of L. LVN exhibited improved dissolution rate compared to L and LCA revealed a sustained release profile. Both these properties are important in designing oral dosage forms for neuropathic pain and bipolar disorder therapy. Further, LCA can be used in the development of extended release drug delivery systems for treating epileptic disorders

Macrocyclic Glycohybrid Toolbox Identifies Novel Antiangiogenesis Agents from Zebrafish Assay

A practical and modular approach to obtain a diverse set of 14-membered macrocyclic compounds from carbohydrates is developed that utilizes functional groups at C-1 and C-5. The evaluation of this toolbox in various zebrafish assays led to the identification of <b>2.7f</b> as an antiangiogenesis agent

Hepatoprotective Cocrystals and Salts of Riluzole: Prediction, Synthesis, Solid State Characterization, and Evaluation

Riluzole is a drug, used to slow the course of amyotrophic lateral sclerosis. Due to its unique structure and functionalities, it is able to form both salts and cocrystals. This is a BCS class II drug with poor solubility and causes hepatotoxicity which limits its application. The present study aims toward development of novel solid forms of riluzole to address the said limitations. Apart from this, an attempt has been made to develop a prediction model using software tools to identify the appropriate synthons for formation of cocrystals. It was observed that out of 33 coformers selected, prediction results were in agreement with the experimental outcome for 25 coformers, which demonstrated the potential of the model developed. Seven new solid forms of riluzole, five cocrystals with ferulic acid, syringic acid, vanillic acid, cinnamic acid, and proline, and two salts with 2,4 dihydroxybenzoic acid and fumaric acid were successfully developed. All the solid forms were characterized by DSC, powder XRD, FTIR, and single crystal XRD. Single crystal X-ray analysis of the all solid form shows R₂²(8) motif between riluzole and coformers through N–H···O and O–H···N bond except riluzole-proline zwitterionic cocrystal. In riluzole-fumaric acid, partial proton transfer of O to N due to acidic H atom disorder has been observed. Dissolution profiles of all the solid forms were comparable to that of plain riluzole, and complete drug release was observed within 60 min for all systems. <i>In vivo</i> hepatotoxicity study with riluzole-ferulic acid and riluzole-syringic acid in mice model revealed its potential hepatoprotective effect to counterattack the hepatotoxic adverse effects of riluzole