P-stereocontrolled synthesis of oligo(nucleoside N3′→O5′ phosphoramidothioate)s – opportunities and limitations

3′-N-(2-Thio-1,3,2-oxathiaphospholane) derivatives of 5′-O-DMT-3′-amino-2′,3′-dideoxy-ribonucleosides (_NOTP-N), that bear a 4,4-unsubstituted, 4,4-dimethyl, or 4,4-pentamethylene substituted oxathiaphospholane ring, were synthesized. Within these three series, _NOTP-N differed by canonical nucleobases (i.e., Ade^Bz, Cyt^Bz, Gua^iBu, or Thy). The monomers were chromatographically separated into P-diastereomers, which were further used to prepare N_NPSN′ dinucleotides (3), as well as short P-stereodefined oligo(deoxyribonucleoside N3′→O5′ phosphoramidothioate)s (NPS-) and chimeric NPS/PO- and NPS/PS-oligomers. The condensation reaction for _NOTP-N monomers was found to be 5–6 times slower than the analogous OTP derivatives. When the 5′-end nucleoside of a growing oligomer adopts a C3′-endo conformation, a conformational ‘clash’ with the incoming _NOTP-N monomer takes place, which is a main factor decreasing the repetitive yield of chain elongation. Although both isomers of N_NPSN′ were digested by the HINT1 phosphoramidase enzyme, the isomers hydrolyzed at a faster rate were tentatively assigned the R_P absolute configuration. This assignment is supported by X-ray analysis of the protected dinucleotide ^DMTdG^iBu_NPSMeT_OAc, which is P-stereoequivalent to the hydrolyzed faster P-diastereomer of dG_NPST.

Separated P-diastereomers of 3′-N-(2-thio-1,3,2-oxathiaphospholane) derivatives of 5′-O-DMT-3′-amino-2′,3′-dideoxy-ribonucleosides were used to prepare P-stereodefined N_NPSN′ dinucleotides and short NPS-, NPS/PO- and NPS/PS-oligomers.     

Reactive molecular dynamics simulation of the high-temperature pyrolysis of 2,2′,2′′,4,4′,4′′,6,6′,6′′-nonanitro-1,1′:3′,1′′-terphenyl (NONA)

2,2′,2′′,4,4′,4′′,6,6′,6′′-Nonanitro-1,1′:3′,1′′-terphenyl (NONA) is currently recognized as an excellent heat-resistant explosive. To improve the atomistic understanding of the thermal decomposition paths of NONA, we performed a series of reactive force field (ReaxFF) molecular dynamics simulations under extreme conditions of temperature and pressure. The results show that two distinct initial decomposition mechanisms are the homolytic cleavage of the C–NO₂ bond and nitro–nitrite (NO₂ → ONO) isomerization followed by NO fission. Bimolecular and fused ring compounds are found in the subsequent decomposition of NONA. The product identification analysis under finite time steps showed that the gaseous products are CO₂, N₂, and H₂O. The amount of CO₂ is energetically more favorable for the system at high temperature or low density. The carbon-containing clusters are a favorable growth pathway at low temperatures, and this process was further demonstrated by the analysis of diffusion coefficients. The increase of the crystal density accelerates the decomposition of NONA judged by the analysis of reaction kinetic parameters and activation barriers. In the endothermic and exothermic stages, a 20% increase in NONA density increases the activation energies by 3.24 and 0.48 kcal mol⁻¹, respectively. The values of activation energies (49.34–49.82 kcal mol⁻¹) agree with the experimental data in the initial decomposition stage.

The bimolecular and fused ring compounds are found in the high-temperature pyrolysis of NONA using ReaxFF molecular dynamics simulations.     

Anti-inflammatory butenolide derivatives from the coral-derived fungus Aspergillus terreus and structure revisions of aspernolides D and G,butyrolactone VI and 4′,8′′-diacetoxy butyrolactone VI

Chemical investigation of the coral-derived fungus Aspergillus terreus led to the discovery of ten butenolide derivatives (1–10), including four new ones (1–4). The new structures were characterized on the basis of comprehensive spectroscopic analysis, including 1D and 2D NMR and HRESIMS data. Compounds 1 and 2 were a pair of rare C-8′′ epimers with vicinal diol motifs. The absolute configurations of 1–4 were determined via [Mo₂(AcO)₄] induced circular dichroism (ICD) spectra and comparison of their experimental ECD spectra. Importantly, the structures of reported aspernolides D and G, butyrolactone VI and 4′,8′′-diacetoxy butyrolactone VI have been correspondingly revised via a combined strategy of experimental validations, ¹³C NMR predictions by ACD/Labs software, and ¹³C NMR calculations. Herein we provide valuable referenced ¹³C NMR data (C-7′′, C-8′′, and C-9′′) for the structure elucidations of butenolide derivatives with 1-(2-hydroxyphenyl)-3-methylbutane-2,3-diol, 2-(2,3-dihydrobenzofuran-2-yl)propan-2-ol, or 2,2-dimethylchroman-3-ol motifs. Additionally, all the isolates (1–10) were assessed for anti-inflammatory activity by measuring the amount of NO production in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages, and compound 10 showed an even stronger inhibitory effect than the postive control indomethacin, presenting it as a promising lead compound for the development of new anti-inflammatory agents.

Chemical investigation of the coral-derived fungus Aspergillus terreus led to the discovery of ten butenolide derivatives (1–10), including four new ones (1–4).     

Synthesis of pyrrolo[3′,2′:4,5][1,3]diazepino[2,1,7-cd]pyrrolizine derivatives from dicyanovinylene-bis(meso-aryl)dipyrrin

Pyrrolo[3′,2′:4,5][1,3]diazepino[2,1,7-cd]pyrrolizine derivatives 2 and 3 were synthesized from dicyanovinylene-bis(meso-aryl)dipyrrin in the presence of either BF₃·OEt₂ or InBr₃, where 2 was readily oxidized in aerobic conditions to be 3. It was understood that the fully elongated π-conjugation of 3 is achieved via the conformation of 2. Crystal structures of 2 and 3 were elucidated by X-ray diffraction analysis. Furthermore, two redox states, 3_ox and 3_red were observed in the chemical redox processes.

Pyrrolo[3′,2′:4,5][1,3]diazepino[2,1,7-cd]pyrrolizine derivatives 2 and 3 were synthesized from dicyasnovinylene-bis(meso-aryl)dipyrrin in the presence of BF₃·OEt₂ or InBr₃. The structures were elucidated by X-ray crystallography.     

Synthesis and photophysical properties of N-alkyl dithieno[3,2-b:2′,3′-d]pyrrole based donor/acceptor-π-conjugated copolymers for solar-cell application

Two kinds of donor–acceptor π-conjugated copolymer based on poly{[N-hexyl-dithieno(3,2-b:2′,3′-d)pyrrole-2,6-diyl]alt-[isoindigo]} (PDTP-IID) and poly{[N-hexyl-dithieno(3,2-b:2′,3′-d)pyrrole-2,6-diyl]alt-[thiazol-2,5-diyl]} (PDTP-Thz) were investigated. These copolymers were synthesized via a Stille coupling reaction. The results showed the structure–property relationships of different donor–acceptor (D–A) combinations. The polymer structures and photophysical properties were characterized by ¹H NMR, TGA, DSC, UV-vis absorption spectroscopy, AFM, CV, and XRD measurement. Through UV-vis absorption and cyclic voltammetry (CV) measurements, it showed that the copolymers exhibit not only a low bandgap of 1.29 eV and 1.51 eV but also a deep highest occupied molecular orbital (HOMO) of −5.49 and −5.11 eV. Moreover, photovoltaic properties in combination with the fullerene derivatives were investigated. The device based on the copolymers with PC₇₁BM exhibited higher maximum power conversion efficiency and higher maximum short-circuit current density of 0.23% with 1.64 mA cm⁻² of PDTP-IID:PC₇₁BM and 0.13% with 1.11 mA cm⁻² of PDTP-Thz:PC₇₁BM than those of the copolymers with PC₆₁BM. Measurements performed for N-hexyl-dithieno(3,2-b:2′,3′-d)pyrrole-based copolymers proved the potential of these polymers to be applied in optoelectronic applications.

The relationships between the structure and the property of donor–acceptor copolymers based on dithieno[3,2-b:2′,3′-d]pyrrole as a strong donor unit and isoindigo or thiazole as acceptor units are successfully studied.     

Synthesis,gene silencing activity,thermal stability,and serum stability of siRNA containing four (S)-5′-C-aminopropyl-2′-O-methylnucleosides (A,adenosine; U,uridine; G,guanosine; and C,cytidine)

Herein, we report the synthesis of (S)-5′-C-aminopropyl-2′-O-methyladenosine and (S)-5′-C-aminopropyl-2′-O-methylguanosine phosphoramidites and the properties of small interfering RNAs (siRNAs) containing four (S)-5′-C-aminopropyl-2′-O-methylnucleosides (A, adenosine; U, uridine; G, guanosine; and C, cytidine). The siRNAs containing (S)-5′-C-aminopropyl-nucleosides at the 3′- and 5′-regions of the passenger strand were well tolerated for RNA interference (RNAi) activity. Conversely, the (S)-5′-C-aminopropyl modification in the central region of the passenger strand decreased the RNAi activity. Furthermore, the siRNAs containing three or four consecutive (S)-5′-C-aminopropyl-2′-O-methylnucleosides at the 3′- and 5′-regions of the passenger strand exhibited RNAi activity similar to that of the corresponding 2′-O-methyl-modified siRNAs. Finally, it was observed that (S)-5′-C-aminopropyl modifications effectively improved the serum stability of the siRNAs, compared with 2′-O-methyl modifications. Therefore, (S)-5′-C-aminopropyl-2′-O-methylnucleosides would be useful for improving the serum stability of therapeutic siRNA molecules without affecting their RNAi activities.

(S)-5′-C-Aminopropyl-2′-O-methylnucleosides would be useful for improving the serum stability of therapeutic siRNA molecules without affecting their RNAi activities.     

LNA units present in [RP-PS]-(DNA#LNA) chimeras enhance the thermal stability of parallel duplexes and triplexes formed with (2′-OMe)-RNA strands

The results of CD measurements indicate that 2-4 LNA units distributed along 12 nt P-stereodefined phosphorothioate [R_P-PS]-(DNA#LNA) chimeras impose a C3′-endo conformation on the 2′-deoxyribonucleosides. Under neutral and slightly acidic conditions homopurine [R_p-PS]-(DNA#LNA) hybridizes with 9–12 nt Hoogsteen-paired (2′-OMe)-RNA strands to form parallel duplexes, which are thermally more stable than the reported earlier analogous complexes containing LNA-free [R_P-PS]-DNA oligomers (ΔT_m = 7 °C per LNA unit at pH 5.4). Upon addition of the corresponding Watson–Crick-paired (2′-OMe)-RNA strands, parallel triplexes are formed with further increased thermal stability.

3′-O-(2-Thio-1,3,2-oxathiaphospholane) derivatives of 5′-O-DMT-LNA-nucleosides were used to prepare P-stereodefined (R_P-PS)-DNA#LNA chimeras, which form thermally stable parallel complexes with (2′-OMe)-RNA matrices.     

Three successive and regiocontroled palladium cross-coupling reactions to easily synthesize novel series of 2,4,6-tris(het)aryl pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidines

The first access to tris(het)arylated pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. The series were generated from 4-chloroaminopyridinium, which afforded the key intermediate bearing three leaving groups, i.e. a C-2 methylsulfanyl, a lactame carbonyl group in C-4 and a chlorine atom in C-6. The regioselective reactions led to the tris(het)aryl derivatives with satisfying to high yields. The three successive cross-coupling reactions occurred first in C-6 by the displacement of chlorine, next in C-4 position by a sequential Pd-catalyzed phosphonium coupling and finally in C-2 under a Pd/Cu-catalyzed desulfitative cross-coupling reaction. The optimization and scope of each reaction are discussed and the original compounds characterized.

The first access to tris(het)arylated pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported.     

Structure-based design and synthesis of a novel long-chain 4′′-alkyl ether derivative of EGCG as potent EGFR inhibitor: in vitro and in silico studies

Herein, we report the discovery of a novel long-chain ether derivative of (−)-epigallocatechin-3-gallate (EGCG), a major green tea polyphenol as a potent EGFR inhibitor. A series of 4′′-alkyl EGCG derivatives have been synthesized via regio-selectively alkylating the 4′′ hydroxyl group in the D-ring of EGCG and tested for their antiproliferative activities against high (A431), moderate (HeLa), and low (MCF-7) EGFR-expressing cancer cell lines. The most potent compound, 4′′-C₁₄ EGCG showed the lowest IC₅₀ values across all the tested cell lines. 4′′-C₁₄ EGCG was also found to be significantly more stable than EGCG under physiological conditions (PBS at pH 7.4). Further western blot analysis and imaging data revealed that 4′′-C₁₄ EGCG induced cell death in A431 cells with shrunken nuclei, nuclear fragmentation, membrane blebbing, and increased population of apoptotic cells where BAX upregulation and BCL_XL downregulation were observed. In addition, autophosphorylation of EGFR and its downstream signalling proteins Akt and ERK were markedly inhibited by 4′′-C₁₄ EGCG. MD simulation and the MM/PBSA analysis disclosed the binding mode of 4′′-C₁₄ EGCG in the ATP-binding site of EGFR kinase domain. Taken together, our findings demonstrate that 4′′-C₁₄ EGCG can act as a promising potent EGFR inhibitor with enhanced stability.

Among the synthesized 4′′-alkyl EGCG derivatives, 4′′-C₁₄ EGCG inhibited EGF stimulated phosphorylation of EGFR and its downstream signaling pathways, ERK and Akt. 4′′-C₁₄ EGCG showed significantly improved stability than EGCG and induced apoptosis.     

Organic binary charge-transfer compounds of 2,2′ : 6′,2′′ : 6′′,6-trioxotriphenylamine and a pyrene-annulated azaacene as donors

Three binary charge-transfer (CT) compounds resulting from the donor 2,2′ : 6′,2′′ : 6′′,6-trioxotriphenylamine (TOTA) and the acceptors F₄TCNQ and F₄BQ and of a pyrene-annulated azaacene (PAA) with the acceptor F₄TCNQ are reported. The identity of these CT compounds are confirmed by single-crystal X-ray diffraction as well as by IR, UV-vis-NIR and EPR spectroscopy. X-ray diffraction analysis reveals a 1 : 1 stoichiometry for TOTA·F₄TCNQ, a 2 : 1 donor : acceptor ratio in (TOTA)₂·F₄BQ, and a rare 4 : 1 stoichiometry in (PAA)₄·F₄TCNQ, respectively. Metrical parameters of the donor (D) and acceptor (A) constituents as well as IR spectra indicate full CT in TOTA·F₄TCNQ, partial CT in (TOTA)₂·F₄BQ and only a very modest one in (PAA)₄·F₄TCNQ. Intricate packing motifs are present in the crystal lattice with encaged, π-stacked (F₄TCNQ⁻)₂ dimers in TOTA·F₄TCNQ or mixed D/A stacks in the other two compounds. Their solid-state UV-vis-NIR spectra feature CT transitions. The CT compounds with F₄TCNQ are electrical insulators, while (TOTA)₂·F₄BQ is weakly conducting.

Three binary charge-transfer (CT) compounds resulting from the donor 2,2′ : 6′,2′′ : 6′′,6-trioxotriphenylamine (TOTA) and the acceptors F₄TCNQ and F₄BQ and of a pyrene-annulated azaacene (PAA) with the acceptor F₄TCNQ are reported.     

In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations

In the present era, there are many efforts trying to face the emerging and successive waves of the COVID-19 pandemic. This has led to considering new and unusual targets for SARS CoV-2. 2′-O-Methyltransferase (nsp16) is a key and attractive target in the SARS CoV-2 life cycle since it is responsible for the viral RNA protection via a cap formation process. In this study, we propose a new potential inhibitor for SARS COV-2 2′-O-methyltransferase (nsp16). A fragment library was screened against the co-crystal structure of the SARS COV-2 2′-O-methyltransferase complexed with Sinefungin (nsp16 – PDB ID: 6WKQ), and consequently the best proposed fragments were linked via a de novo approach to build molecule AP-20. Molecule AP-20 displayed a superior docking score to Sinefungin and reproduced the key interactions in the binding site of 2′-O-methyltransferase. Three molecular dynamic simulations of the 2′-O-methyltransferase apo structure and its complexed forms with AP-20 and Sinefungin were performed for 150 nano-seconds to provide insights on the dynamic nature of such setups and to assess the stability of the proposed AP-20/enzyme complex. AP-20/enzyme complex demonstrated better stability for the ligand–enzyme complex compared to Sinefungin in a respective setup. Furthermore, MM-PBSA binding free energy calculations showed a better profile for AP-20/enzyme complex compared to Sinefungin/enzyme complex emphasizing the potential inhibitory effect of AP-20 on SARS COV-2 2′-O-methyltransferase. We endorse our designed molecule AP-20 to be further explored via experimental evaluations to confront the spread of the emerging COVID-19. Also, in silico ADME profiling has ascribed to AP-20 an excellent safety and metabolic stability profile.

The identification of AP-20 as a potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations.     

Elucidating the intramolecular contrast in the STM images of 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules recorded at room-temperature and at the liquid-solid interface

Star-shaped 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules self-assemble at the solid–liquid interface into a compact hexagonal nanoarchitecture on graphite. High resolution scanning tunneling microscopy (STM) images of the molecules reveal intramolecular features. Comparison of the experimental data with calculated molecular charge density contours shows that the molecular features in the STM images correspond to molecular LUMO+2.

Intramolecular contrast in the STM images of 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules recorded at room-temperature and at the liquid–solid interface.     

Convenient construction of tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles and tetrahydroindolizino[8,7-b]indoles via one-pot domino reaction

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes. Under similar conditions, the one-pot reaction of tryptamines, alkyl propiolates and β-nitroalkenes resulted in functionalized tetrahydroindolizino[8,7-b]indoles. The reaction mechanism involved sequential generation of β-enamino ester, Michael addition, Pictet–Spengler reaction and annulation process. The reaction showed high atomic economy and met the goals of sustainable chemistry.

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes.     

Synthesis and evaluation of (S)-5′-C-aminopropyl and (S)-5′-C-aminopropyl-2′-arabinofluoro modified DNA oligomers for novel RNase H-dependent antisense oligonucleotides

We designed and synthesized two novel thymidine analogs: (S)-5′-C-aminopropyl-thymidine and (S)-5′-C-aminopropyl-2′-β-fluoro-thymidine. Then, DNA oligomers containing these analogs were synthesized, and their functional properties were evaluated. Compared with the naturally occurring thymidine, it was revealed that (S)-5′-C-aminopropyl-2′-arabinofluoro-thymidine was sufficiently thermally stable, while (S)-5′-C-aminopropyl-thymidine featured thermal destabilization. The difference in thermal stability resulted from a moderate change in the secondary structure of the DNA/RNA duplexes and a molecular fluctuation in monomers derived from the (S)-5′-C-aminopropyl side chain, as well as from a variation in sugar puckering derived from the 2′-arabinofluoro modification. Meanwhile, the incorporation of these analogs significantly enhanced the nuclease resistance of the DNA oligomers. Moreover, the (S)-5′-C-aminopropyl-2′-arabinofluoro-modified DNA/RNA duplexes showed a superior ability to activate RNase H-mediated cleavage of the RNA strand compared to the (S)-5′-C-aminopropyl-modified DNA/RNA duplexes.

We designed and synthesized two novel thymidine analogs: (S)-5′-C-aminopropyl-thymidine and (S)-5′-C-aminopropyl-2′-β-fluoro-thymidine.     

Highly efficient redox reaction between potassium permanganate and 3,3′,5,5′-tetramethylbenzidine for application in hydrogen peroxide based colorimetric assays

Potassium permanganate (KMnO₄) is one of the most important oxidants, which plays important roles in many fields. Here, we found that KMnO₄ could directly induce the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) to generate an oxidized product with a color change. This redox reaction is highly efficient, and 1 μM KMnO₄ is enough to cause detectable changes in the absorbance signal. Meanwhile, this reaction is very fast and the generated blue product can stabilize for a relatively long period, which has great advantages in practical applications. Since hydrogen peroxide (H₂O₂) is able to react with KMnO₄ under acidic conditions, the KMnO₄-TMB system can be used for the detection of H₂O₂; the absorbance signal induced by 5 μM H₂O₂ can be easily detected in this method. Meanwhile, the KMnO₄-TMB system can also be used for the detection of glucose by monitoring the generation of H₂O₂, which is the main product of glucose oxidation; this method permits detection of concentrations as low as 10 μM glucose, and the sensitivity is comparable to or higher than most peroxidase mimetic based methods, but avoiding the preparation and storage of the nanomaterials. Furthermore, the KMnO₄-TMB system can even be used for analyzing glucose in serum samples, which can also be expected to be used in immunoassays.

The redox reaction between potassium permanganate and 3,3′,5,5′-tetramethylbenzidine is fast and highly efficient, which can be used for different biosensing.     

Appraisal of novel azomethine–thioxoimidazolidinone conjugates as ecto-5′-nucleotidase inhibitors: synthesis and molecular docking studies

Purinergic signaling is regulated by a group of extracellular enzymes called ectonucleotidases. One of its members i.e., ecto-5′-nucleotidase (h-e5′NT) is involved in the final step of the enzymatic hydrolysis cascade that is the conversion of adenosine monophosphate (AMP) to adenosine and therefore, involves the regulation of adenosine level in extracellular space. The overexpression of h-e5′NT has been observed in various pathological conditions such as hypoxia, inflammation and cancers, and led to various complications. Hence, the identification of a potent as well as selective inhibitor of h-e5′NT is of greater importance in therapeutic treatment of various diseases. Azomethine-thioxoimidazolidinone derivatives were studied for their inhibition potential against e5′NT enzyme along with cytotoxic potential against cancer cell lines possessing overexpression of e5′NT enzyme. The derivative (E)-3-((4-((3-methoxybenzyl)oxy)benzylidene)amino)-2-thioxoimidazolidin-4-one (4g) displayed selective and significant inhibition towards h-e5′NT with an IC₅₀ value of 0.23 ± 0.08 μM. While two other derivatives i.e., (E)-3-(((5-bromothiophen-2-yl)methylene)amino)-2-thioxoimidazolidin-4-one (4b) and 2-thioxo-3-((3,4,5-trimethoxybenzylidene)amino)imidazolidin-4-one (4e), exhibited non-selective potent inhibitory behavior against both human and rat enzymes. Moreover, these derivatives (4b, 4e and 4g) were further investigated for their effect on the expression of h-e5′NT using quantitative real time polymerase chain reaction. Additionally, molecular docking and DFT studies were also performed to determine the putative binding mode of potent inhibitors within the enzyme active site. HOMO, LUMO, ΔE, and molecular electrostatic potential maps were computed by DFT and the charge transfer regions within the molecules were identified to find out the regions for electrophilic and nucleophilic attack.

Azomethine–thioxoimidazolidinone conjugates as ecto-5′-nucleotidase inhibitors.     

Synthesis of pyrazolo[5′,1′:2,3]imidazo[1,5-c]quinazolin-6(5H)-ones and molecular docking study of their affinity against the COVID-19 main protease

A novel series of fused pyrazolo[5′,1′:2,3]imidazo[1,5-c]quinazolin-6(5H)-ones were synthesized and their affinity against the COVID-19 main protease was investigated using molecular docking study and compared to that of some used standard clinical drugs. These compounds were obtained in good to excellent yields from 63 to 91% in the presence of 30 mol% catalyst in ethanol at reflux for 2 h through an efficient one-pot three-component reaction including an intramolecular rearrangement and a cyclization through intramolecular nucleophilic reaction. The results of in silico studies showed that electronegativity, resonance effects, hydrophobic interaction, halogen and hydrogen bonding had significant effects on the performance of these compounds as an inhibitor ligand. Also, these results indicated the proper affinity of these compounds against the COVID-19 main protease with excellent binding energies (especially 4r = −8.77, 4q = −8.73 and 4m = −8.63) in comparison to remdesivir, chloroquine, hydroxychloroquine, molnupiravir and nirmatrelvir drugs.

A novel series of fused pyrazolo[5′,1′:2,3]imidazo[1,5-c]quinazolin-6(5H)-ones were synthesized and their affinity against the COVID-19 main protease was investigated using molecular docking study and compared to that of some used clinical drugs.     

Synthesis and characterisation of κ2-N,O-oxazoline-enolate complexes of nickel(ii): explorations in coordination chemistry and metal-mediated polymerisation

The synthesis and characterisation (UV-Vis, IR, X-ray diffraction, etc.) of a series of Ni(ii) complexes derived from both known and novel 2-acylmethyl-2-oxazolines (2a–g: i.e., (Z)-1-R-2-(4,4′-dimethyl-2′-oxazolin-2′-yl)eth-1-en-1-ol; R = –Ph, –2-furanyl, –p-NO₂-Ph, –t-Bu, –2-thiofuranyl, p-NC-Ph, –CF₃) is reported. These Ni materials (3a–g) represent the first group 10 metal complexes of this ligand class. All derivatives reported are paramagnetic (S = 1) compounds of formulae Ni(κ²-N,O-L)₂ where L represents an enolate of structure (Z)-1-R-2-(4′,4′-dimethyl-2′-oxazolin-2′-yl)eth-1-en-1-ate formed via proton loss from 2. The air- and moisture-stable metal complexes feature a less typical distorted seesaw-shaped disposition of binding atoms around the metal centre for six structurally characterised (X-ray) examples. Preliminary investigations indicate that 3a (R = –Ph) is a useful catalysts for olefin polymerisation in the presence of alkylaluminum reagents.

Novel Ni(ii) enolate complexes derived from (Z)-1-R-2-(4′,4′-dimethyl-2′-oxazolin-2′-yl)eth-1-en-1-ols are synthesised and structurally examined. The complexes display good potency as olefin polymerisation catalysts.     

Synthesis and molecular modeling studies of cholinesterase inhibitor dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines]

A set of dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines] 8a–l was regioselectively synthesized utilizing multi-component azomethine cycloaddition reaction of 3-(arylmethylidene)pyrrolidine-2,5-diones 5a–e, isatins 6a–c and sarcosine 7. Single crystal X-ray studies of 8c add conclusive support for the structure. Compounds 8e and 8g reveal cholinesterase inhibitory properties with promising efficacy against both AChE and BChE and were found to be more selective towards AChE than BChE as indicted by the selectivity index like Donepezil (a clinically used cholinesterase inhibitory drug). Molecular modeling studies assist in understanding the bio-observations and identifying the responsible parameters behind biological properties.

Dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines] were regioselectively synthesized revealing cholinesterase (AChE, BChE) inhibitory properties.