Chromone-embedded peptidomimetics and furopyrimidines as highly potent SARS-CoV-2 infection inhibitors: docking and MD simulation study.

BACKGROUND: COVID-19 is a respiratory illness caused by SARS-CoV-2. Pharmaceutical companies aim to control virus spread through effective drugs. This study investigates chromone compound derivatives' ability to inhibit viral entry and prevent replication. METHOD: This study investigated the inhibitory effect of chromone-embedded peptidomimetics and furopyrimidines on 7BZ5 from Severe Acute Respiratory Syndrome CoV-2, Homo sapiens, and 6LU7 from Bat SARS-like CoV using molecular docking. The crystal structure of these proteins was obtained from the Protein Data Bank, and the inhibition site was determined using ligand binding interaction options. The 3D structure was protonated and energetically minimised using MOE software. Chromone derivatives were designed in three dimensions, and their energy was minimised using MOE 2019. The molecular drug-likeness was calculated using SwissADME, Lipinski and Benigni-Bossa's rule, and toxicity was calculated using Toxtree v3.1.0 software. Compounds with pharmacological properties were selected for molecular docking, and interactions were assessed using MOE 2019. MD simulations of Mpro-ch-p complexes were performed to evaluate root mean square fluctuations (RMSF) and measure protein stability. RESULT: The pharmacokinetic tests revealed that chromone derivatives of the peptidomimetic family have acceptable pharmacokinetic activity in the human body. Some compounds, such as Ch-p1, Ch-p2, Ch-p6, Ch-p7, Ch-p12, and Ch-p13, have pronounced medicinal properties. Molecular docking revealed high affinity for binding to SARS-CoV-2 protease. Ch-p7 had the highest binding energy, likely due to its inhibitory property. A 10 ns molecular dynamics study confirmed the stability of the protein-ligand complex, resulting in minimal fluctuations in the system's backbone. The MM-GBSA analysis revealed free energies of binding of - 19.54 kcal/mol. CONCLUSIONS: The study investigated the inhibition of viral replication using chromone derivatives, finding high inhibitory effects in the peptidomimetic family compared to other studies.

Uncatalyzed diastereoselective synthesis of alkyliminofurochromone-derived benzylmalononitriles via a three-component cascade reaction: competition between Diels-Alder cycloaddition and Michael addition.

Diastereoselective Michael addition reactions of 3-(alkylamino)-9H-furo[3,4-b]chromen-9-one intermediate, produced from the [1 + 4] cycloaddition/tautomerization reaction between 3-formylchromones and alkyl isocyanide in dry CH2Cl2, with arylidene malononitrile were developed to afford a wide range of functionalized 2-((S)-((R,Z)-3-(alkylimino)-9-oxo-3,9-dihydro-1H-furo[3,4-b]chromen-1-yl)(aryl)methyl)malononitrile derivatives in good yields and excellent diastereoselectivities under mild conditions. Excellent diastereoselectivity has been achieved to yield products containing two stereogenic carbons and one stereogenic imine group. Two C-C and one C-O bonds were selectively formed to provide new alkylated iminofurochromones in good yields.

Substrate-controlled selectivity switch in a three-component reaction: sequential synthesis of spiro-oxazolidinedione-cyclopentenones and hydroxy enaminobarbiturates in water.

An efficient eco-friendly catalyst-free three-component domino multicyclization for the synthesis of new spirobicyclic oxazolidinedione containing cyclopentenone moieties has been established by mixing amines, ß-dicarbonyl compounds and N,N'-dimethylalloxan in water at room temperature. This domino process involves multiple reactions such as enamination/aldol-like reaction/Stork enamine annulation/intramolecular cyclization under mild conditions.

Pseudo-five-component reaction between 3-formylchromones, meldrum's acid, isocyanides and primary arylamines: diversity-oriented synthesis of novel chromone-containing peptidomimetics.

An efficient and practical method has been developed for the diversity-oriented synthesis of chromone-containing tripeptides via pseudo-five-component reaction between 3-formylchromones, Meldrum's acid, isocyanides and primary aromatic amines for the generation of a wide range of structurally interesting and pharmacologically significant compounds at ambient temperature. It is worth mentioning that in the course of this reaction, five new bonds (two C-C bonds, two C-N bonds and one C═O bond) are formed. In the present reaction three amide bonds are newly formed.

Simple synthesis of 7H-phenaleno[1,2-b]furan-7-one derivatives by one-pot, three-component reactions.

The reaction of alkyl isocyanides with various aldehydes and 3-hydroxy-1 H-phenalene-1-one is described. The protocol offers facile and efficient synthesis of biologically interesting 9-(alkyl or arylamino)-7 H-phenaleno[1,2- b]furan-7-one derivatives from readily available starting materials in high yields.

Antitumor activity of 6-(cyclohexylamino)-1, 3-dimethyl-5(2-pyridyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione and Its Ti(IV), Zn(II), Fe(III), and Pd(II) complexes on K562 and Jurkat cell lines.

(6-(cyclohexylamino)-1,3-dimethyl-5(2-pyridyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione) abbreviated as CDP was synthesized and characterized. Ti(IV), Zn(II), Fe(III), and Pd(II) metal complexes of this ligand are prepared by the reaction of salts of Ti(IV), Zn(II), Fe(III), and Pd(II) with CDP in acetonitrile. Characterization of the ligand and its complexes was made by microanalyses, FT-IR, (1)H NMR, (13)C NMR, and UV-Visible spectroscopy. All complexes were characterized by several techniques using elemental analysis (C, H, N), FT-IR, electronic spectra, and molar conductance measurements. The elemental analysis data suggest the stoichiometry to be 1:1 [M:L] ratio formation. The molar conductance measurements reveal the presence of 1:1 electrolytic nature complexes. These new complexes showed excellent antitumor activity against two kinds of cancer cells that are K562 (human chronic myeloid leukemia) cells and Jurkat (human T lymphocyte carcinoma) cells.

Shaken not stirred: a facile synthesis of 1,4-bis(furo[2,3-d]-pyrimidine-2,4(1H,3H)-dione-5-yl)benzenes by one-pot reaction of isocyanides, N,N'-dimethylbarbituric acid, and terephthaldialdehyde.

A simple and efficient synthesis of 1,4-bis(furo[2,3-d]pyrimidine-2,4(1H,3H)-dione-5-yl)benzene derivatives was achieved via a one-pot three-component reaction of isocyanides, N,N'-dimethylbarbituric acid, and terephthaldialdehyde in DMF at room temperature for 30 min. These improved reaction conditions allow the preparation of highly substituted furopyrimidinones in high yields and purity under mild reaction conditions.

Introducing a novel class of four-component reactions.

A novel four-component reaction approach to the efficient synthesis of triamide and amidodiester derivatives using amines or alcohols, aldehydes and alkyl or aryl isocyanides in the presence of Meldrum's acid as a CH acid, instead of carboxylic acid of Ugi four-component reaction, was studied.