Synthesis of Novel 1-Oxo-2,3,4-trisubstituted Tetrahydroisoquinoline Derivatives, Bearing Other Heterocyclic Moieties and Comparative Preliminary Study of Anti-Coronavirus Activity of Selected Compounds.

A series of novel 1-oxo-2,3,4-trisubstituted tetrahydroisoquinoline (THIQ) derivatives bearing other heterocyclic moieties in their structure were synthesized based on the reaction between homophthalic anhydride and imines. Initial studies were carried out to establish the anti-coronavirus activity of some of the newly obtained THIQ-derivatives against two strains of human coronavirus-229E and OC-43. Their antiviral activity was compared with that of their close analogues, piperidinones and thiomorpholinones, previously synthesized in our group, with aim to expand the range of the tested representative sample and to obtain valuable preliminary information about biological properties of a wider variety of compounds.

Precious metal-free molecular machines for solar thermal energy storage.

Four benzothiazolium crown ether-containing styryl dyes were prepared through an optimized synthetic procedure. Two of the dyes (4b and 4d) having substituents in the 5-position of the benzothiazole ring are newly synthesized compounds. They demonstrated a higher degree of trans-cis photoisomerization and a longer life time of the higher energy forms in comparison with the known analogs. The chemical structures of all dyes in the series were characterized by NMR, UV-vis, IR spectroscopy and elemental analysis. The steady-state photophysical properties of the dyes were elucidated. The stability constants of metal complexes were determined and are in good agreement with the literature data for reference dyes. The temporal evolution of trans-to-cis isomerization was observed in a real-time regime. The dyes demonstrated a low intrinsic fluorescence of their Ba2+ complexes and high yield of E/Z photoisomerization with lifetimes of the higher energy form longer than 500 seconds. Density functional theory (DFT) calculations at the B3LYP/6-31+G(d,p) level were performed in order to predict the enthalpies (H) of the cis and trans isomers and the storage energies (ΔH) for the systems studied.

Halogen-containing thiazole orange analogues - new fluorogenic DNA stains.

Novel asymmetric monomeric monomethine cyanine dyes 5a-d, which are analogues of the commercial dsDNA fluorescence binder thiazole orange (TO), have been synthesized. The synthesis was achieved by using a simple, efficient and environmetally benign synthetic procedure to obtain these cationic dyes in good to excellent yields. Interactions of the new derivatives of TO with dsDNA have been investigated by absorption and fluorescence spectroscopy. The longest wavelength absorption bands in the UV-vis spectra of the target compounds are in the range of 509-519 nm and these are characterized by high molar absorptivities (63000-91480 L·mol-1·cm-1). All investigated dyes from the series are either not fluorescent or their fluorescence is quite low, but they become strongly fluorescent after binding to dsDNA. The influence of the substituents attached to the chromophores was investigated by combination of spectroscopic (UV-vis and fluorescence spectroscopy) and theoretical (DFT and TDDFT calculations) methods.

Novel Tetrahydroisoquinoline-Based Heterocyclic Compounds Efficiently Inhibit SARS-CoV-2 Infection In Vitro.

The ongoing COVID-19 pandemic has caused over six million deaths and huge economic burdens worldwide. Antivirals against its causative agent, SARS-CoV-2, are in urgent demand. Previously, we reported that heterocylic compounds, i.e., chloroquine (CQ) and hydroxychloroquine (HCQ), are potent in inhibiting SARS-CoV-2 replication in vitro. In this study, we discussed the syntheses of two novel heterocylic compounds: tert-butyl rel-4-(((3R,4S)-3-(1H-indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate (trans-1) and rel-(3R,4S)-3-(1H-indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2H)-one (trans-2), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound trans-1 showed higher anti-SARS-CoV-2 activity than trans-2, with a half maximal effective concentration (EC50) of 3.15 µM and a selective index (SI) exceeding 63.49, which demonstrated comparable potency to CQ or HCQ. Additional anti-SARS-CoV-2 tests on Calu-3 human lung cells showed that trans-1 efficiently inhibited viral replication (EC50 = 2.78 µM; SI: > 71.94) and performed better than CQ (EC50 = 44.90 µM; SI = 2.94). The time of an addition assay showed that the action mechanism of trans-1 differed from that of CQ, as it mainly inhibited the post-entry viral replication in both Vero E6 and Calu-3 cells. In addition, the differences between the antiviral mechanisms of these novel compounds and CQ were discussed.

(S)-Methyl 2-[(3R,4R)-2-benzyl-3-(2-fur-yl)-1-oxo-1,2,3,4-tetra-hydro-isoquinoline-4-carboxamido]-3-(1H-indol-3-yl)propanoate.

The title compound, C(33)H(29)N(3)O(5), was synthesized by the reaction of racemic trans-2-benzyl-3-(2-fur-yl)-1-oxo-1,2,3,4-tetra-hydro-isoquinoline-4-carboxylic acid, l-tryptophan methyl ester and diisopropylcarbodiimide in dry dichloro-methane. The furan ring is disordered over two positions in a 0.859 (14):0.141 (14) ratio. In the 1,2,3,4-tetra-hydro-iso-quin-oline ring system, the heterocyclic ring is not planar, with puckering parameters Q(T) = 0.448 (2) Å, θ = 64.9 (3) and ϕ = 268.3 (3)°. The crystal is extended into a three-dimensional supra-molecular architecture through inter-molecular N-H⋯O hydrogen bonds and C-H⋯π inter-actions. The absolute structure was assigned by reference to the chiral starting material.

Methyl trans-(±)-1-oxo-2-phenethyl-3-(thio-phen-2-yl)-1,2,3,4-tetra-hydro-isoquinoline-4-carboxyl-ate.

In the title compound, C(23)H(21)NO(3)S, the piperidine ring of the tetra-hydro-isoquinolinone unit adopts a screw-boat conformation. The thio-phene ring is disordered in a 0.700 (3):0.300 (3) ratio by an approximate 180° rotation of the ring around the C-C bond linking the ring to the tetra-hydro-isoquinolinone unit. The benzene ring of the tetra-hydro-isoquinolinone unit makes dihedral angles of 83.1 (2) and 62.38 (11)° with the major occupancy thio-phene ring and the phenyl ring, respectively. The dihedral angle between the phenyl ring and the thio-phene ring is 71.0 (2)°. In the crystal structure, mol-ecules are linked together by inter-molecular C-H⋯O and C-H⋯π inter-actions.

Methyl trans-rac-2-hexyl-1-oxo-3-(2-pyrid-yl)-1,2,3,4-tetra-hydroisoquinoline-4-carboxyl-ate.

The title compound, C(22)H(26)N(2)O(3), was synthesized by esterification of trans-rac-2-hexyl-1-oxo-3-(2-pyrid-yl)-1,2,3,4-tetra-hydro-isoquinoline-4-carboxylic acid in the presence of H(2)SO(4) in methanol. The dihedral angle between the benzene and pyridine rings is 84.46 (17)°. The piperidine ring adopts a screw-boat conformation. In the crystal, inversion dimers linked by two C-H⋯O bonds occur.

trans-rac-[1-Oxo-2-phenethyl-3-(2-thien-yl)-1,2,3,4-tetra-hydro-isoquinolin-4-yl]methyl 4-methyl-benzene-sulfonate.

The title compound, C(29)H(27)NO(4)S(2), was synthesized by reaction of trans-rac-4-(hydroxy-meth-yl)-2-phenethyl-3-(thio-phen-2-yl)-3,4-dihydro-isoquinolin-1(2H)-one and 4-methyl-benzene-1-sulfonyl chloride in the presence of Et(3)N in CH(2)Cl(2). The relative orientations of the benzene ring (A) of the 3,4-dihydro-isoquinolinone ring system, the thio-phene ring (B), the benzene ring (C) of the methyl-benzene group and the phenyl ring (D) result in the following dihedral angles: A/B = 80.91 (16), A/C = 22.79 (18), A/D = 9.9 (2), B/C = 80.73 (19), B/D = 88.9 (2) and C/D = 29.9 (2)°. The crystal structure is stabilized by weak inter-molecular C-H⋯O hydrogen bonds and C-H⋯π inter-actions.

Preliminary evaluation of antimicrobial activity of diastereomeric cis/trans-3-aryl(heteroaryl)-3,4-dihydroisocoumarin-4-carboxylic acids.

Preliminary differentiating screening of the antibacterial and antifungal activity of a series of diastereomeric cis/trans-3-aryl(heteroaryl)-3,4-dihydroisocoumarin-4-carboxylic acids (3a-i) was performed by the agar diffusion method against twelve microorganism strains of different taxonomic groups. S. aureus and A. niger were the most sensitive strains to the antibiotic effect of the tested compounds, both inhibited by 10 of 12 compounds. The most potent antibacterial agent was cis-3-phenyl-3,4-dihydroisocoumarin-4-carboxylic acid (cis-3a), exhibiting activity against all seven bacterial test strains.

Synthesis of new trans-2-benzyl-3-(furan-2-yl)-4-substituted-1,2,3,4-tetrahydroisoquinolinones.

The reaction of homophthalic anhydride and N-(furan-2-yl-methylidene)- benzylamine in different solvents and varying temperatures was studied in detail. Mixtures of the expected trans- and cis-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids trans-5 and cis-5, along with by-products 6 and 7 were obtained in dichloroethane or benzene. In pyridine, used for the first time, the reaction became completely diastereoselective, giving only the trans isomer. The carboxylic acid group of trans-5 was transformed in four steps into cyclic aminomethyl groups which yielded various new tetrahydroisoquinolinones trans- 11a-g, incorporating both a known fragment of pharmacological interest and various pharmacophoric substituents.