One-pot Synthetic Approaches for the Construction of Isochroman-4-ones and Benzoxazin-3-ones Using O,P-Acetals

A method for synthesizing six-membered heterocyclic compounds was developed based on the features of O,P-acetals. Sequential reactions of intramolecular cyclization between the methylene carbon atom of O,P-acetal and its electrophilic functional group (ester or protected carbamate) was followed by Horner-Wadsworth-Emmons (HWE) olefination with various aldehydes. The developed one-pot method yielded isochroman-4-one and benzoxazin-3-one derivatives with an alkylidene moiety.

Crystal structure of 2-[(naphthalen-2-yl)methyl]isothiouronium bromide

Herein we report the crystal structure of 2-[(naphthalen-2-yl)methyl]isothiouronium bromide, C12H13N2S+·Br−, which crystallizes in the monoclinic P21/c centrosymmetric space group. The asymmetric unit contains one 2-[(naphthalen-2-yl)methyl]isothiouronium cation and one bromide anion. The methylene carbon lies in plane of the naphthalene core. In comparison with reference structures, elongation of C—S bonds as well as tilting of the isothiouronium group is observed. Given the ionic nature of the compound, the structure is held by charge-assisted N—H...Br hydrogen bonds, with a noteworthy contribution of dipole–dipole interactions, which form bilayers in the structure. The bilayers are held by the weak London forces.

Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.

Novel Quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione Derivatives Against Chloroquine-resistant Plasmodium falciparum

Introduction: In this work DHPMs were combined with the quinoline nucleus to obtain new quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione compounds with improved antiplasmodial activity as well as decreased cytotoxicity. Nineteen quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives connected by a linker group to quinolone ring moieties with different substituents were synthesized and assayed against P. falciparum. Materials and Methods: Nineteen quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives connected by a linker group to quinoline ring moieties with different substituents were synthesized and assayed against chloroquine-resistant Plasmodium falciparum, along with the reference drug chloroquine. Among these compounds, the derivatives with two methylene carbon spacers showed the best activity accompanied by low cytotoxicity. Results: The derivative without substituents on the aromatic ring (2a) and the derivative with a chlorine group at position 4 (2d) provided the best results, with IC50 = 1.15 µM and 1.5 µM, respectively. Conclusion: Compared to the parent drugs, these compounds presented marked decreases in cytotoxicity, with MDL50 values over 1,000 µM and selectivity indexes of >869.5 and >666.6, respectively. The quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione framework appears to be promising for further studies as an antimalarial for overcoming the burden of resistance in P. falciparum.

Crystal structure of 1-butyl-3-{2-[(indan-5-yl)amino]-2-oxoethyl}-1H-imidazol-3-ium chloride

In the cation of the title molecular salt, C18H24N3O+·Cl−, an intramolecular C—H...O hydrogen bond stabilizes the almost coplanar orientation of the aromatic ring of the indane unit and the amide plane. In the crystal, the packing is dominated by intermolecular C—H...Cl hydrogen-bonding interactions that result in the formation of slab-like structures propagating along [010]. The slabs are linked by weak C—H...O interactions, forming layers lying parallel to (100). The methylene carbon atom of the indanyl substituent is disordered over two positions with a refined occupancy ratio of 0.84 (2):0.16 (2). The crystal studied was refined as a twin with matrix [1 0 0.9, 0 \overline{1} 0, 0 0 \overline{1}]; the resulting BASF value is 0.30.

Copper-Catalyzed Tandem Multi-Component Approach to 1,3-Oxazines at Room Temperature by Cross-Dehydrogenative Coupling Using Methanol as C1 Feedstock

A copper(II)-catalyzed multi-component one-pot approach for the synthesis of 1,3-oxazines at room temperature is reported here. Methanol is used as the solvent as well as the carbon source. The methylene carbon of the oxazine product comes from methanol via formaldehyde. tert-Butyl hydroperoxide is used as the oxidant. The reaction uses an environmentally benign metal catalyst and oxidant. No inert atmosphere or precaution is required for the reaction. Most importantly, the reaction avoids the use of carcinogenic formaldehyde.

Anhydrous Aluminum Chloride Catalyzed Methylene Group Inclusion: Mechanistic, Spectral and Single Crystal X-Ray Structural Study on Methanediyl Bis(Cyclohexylmethylcarbamodithioate)

In this study anhydrous AlCl3is used as a catalyst for the inclusion of a methylene group in to cyclohexylmethyldithiocarbamic acid to form methanediyl bis(cyclohexylmethylcarbamodithioate). Dichloromethane is used as a methylene group bearer in the reaction. A suitable mechanistic pathway involving+CH2Cl is discussed. FTIR, NMR and Mass spectral techniques have been used in the analysis. Single crystal X-ray structure of the compound was determined. FTIR spectrum of the compound showed υc-sband at 1073 cm-1and υC-Hvibrations appeared at 2853 and 2928 cm-1. Thioureide stretching band was observed at 1473 cm-1. The molecular ion peak in the Mass spectroscopy confirmed the proposed formula. H1NMR spectrum of the compound showed a signal at 4.33(s) ppm for α-CH of the cyclohexyl ring and -CH3protonsattached to nitrogen appeared at 3.40 ppm. Methylene proton (S-CH2-S) signal appeared at 3.16 ppm which is largely deshielded by the presence of two electronegative sulphur atoms on either side. The characteristic methylene carbon (S-CH2-S) signal appeared at 45.46 ppm in the13C NMR spectrum. Single crystal X-ray structural analysis of the compound showed it to be monomeric. Methylene carbon in S-CH2-S, C(9) is tetrahedrally bonded to two hydrogen atoms and two sulphur atoms S(2), S(3). The molecule stacks its cyclohexyl rings along ‘c’ axis of the unit cell. Short contacts in the form of supramolecular interactions such as C---S and S---S exist in the solid state at 3.49 and 3.50 Å respectively.

Synthesis and characterization of some new fluoroquinolone-barbiturate hybrid systems

New hybrid molecules containing fluoroquinolone-barbiturate moieties were synthesized via simple routes, followed by characterization using various spectroscopic approaches. The THF solvent molecule was incorporated into compounds 2 and 3 through its oxygen atom based on its nucleophilicity. Facile displacement of the chloride ion in 4-oxoquinoline-3-carbonyl chloride by the nucleophilic methylene carbon of 1,3-dialkylbarbiturate/thiobarbiturate afforded the respective hybrids 5 and 6.