ABSTRACT
A new variation of Prins cyclization to directly and stereoselectively synthesize cis-2,6-disubstituted tetrahydropyran-4-ones from 3-chlorohomoallylic alcohols and aldehydes catalyzed by perrhenic acid is reported. The reaction is generally compatible with a range of aliphatic and aromatic aldehydes and 24 examples of tetrahydropyran-4-one products have been prepared in moderate to good yields. This methodology highlights the use of simple starting materials and commercially available aqueous perrhenic acid as a catalyst for Prins cyclization reactions to directly synthesize 2,6-disubstituted tetrahydropyran-4-ones.
Subject(s)
Alcohols , Aldehydes , Cyclization , CatalysisABSTRACT
In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from -7.06 to -10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(4â³-cyanophenyl)-aminoquinoline and 4-(4'-cyanophenoxy)-2-(4â³-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.
Subject(s)
COVID-19 Drug Treatment , Quinolines , Cysteine Endopeptidases/chemistry , Humans , Lactams , Leucine , Molecular Docking Simulation , Nitriles , Peptide Hydrolases , Proline , Quinolines/pharmacology , SARS-CoV-2 , Viral Proteins/metabolismABSTRACT
New target molecules, namely, 2-phenylamino-4-phenoxyquinoline derivatives, were designed using a molecular hybridization approach, which was accomplished by fusing the pharmacophore structures of three currently available drugs: nevirapine, efavirenz, and rilpivirine. The discovery of disubstituted quinoline indicated that the pyridinylamino substituent at the 2-position of quinoline plays an important role in its inhibitory activity against HIV-1 RT. The highly potent HIV-1 RT inhibitors, namely, 4-(2',6'-dimethyl-4'-formylphenoxy)-2-(5â³-cyanopyridin-2â³ylamino)quinoline (6b) and 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(5â³-cyanopyridin-2â³ylamino)quinoline (6d) exhibited half-maximal inhibitory concentrations (IC50) of 1.93 and 1.22 µM, respectively, which are similar to that of nevirapine (IC50 = 1.05 µM). The molecular docking results for these two compounds showed that both compounds interacted with Lys101, His235, and Pro236 residues through hydrogen bonding and interacted with Tyr188, Trp229, and Tyr318 residues through π-π stacking in HIV-1 RT. Interestingly, 6b was highly cytotoxic against MOLT-3 (acute lymphoblastic leukemia), HeLA (cervical carcinoma), and HL-60 (promyeloblast) cells with IC50 values of 12.7 ± 1.1, 25.7 ± 0.8, and 20.5 ± 2.1 µM, respectively. However, 6b and 6d had very low and no cytotoxicity, respectively, to-ward normal embryonic lung (MRC-5) cells. Therefore, the synthesis and biological evaluation of 2-phenylamino-4-phenoxyquinoline derivatives can serve as an excellent basis for the development of highly effective anti-HIV-1 and anticancer agents in the near future.
Subject(s)
HIV Reverse Transcriptase/chemistry , Models, Molecular , Quinolines/chemistry , Reverse Transcriptase Inhibitors/chemistry , Binding Sites , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Humans , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Quinolines/chemical synthesis , Quinolines/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A simple and unified synthesis of four related pyranonaphthoquinone natural products, e.g. 8-O-methylfusarubin, 8-O-methylanhydrofusarubin, fusarubin and anhydrofusarubin, is reported. The key synthetic features include the precedented Diels-Alder cycloaddition to assemble the naphthalene skeleton, selective formylation and acetonylation and intramolecular acetalization to construct the pyran ring. Manipulation of the oxidation state of the naphthoquinone core was performed to construct the two analogues, fusarubin and anhydrofusarubin. This work also highlights an unprecedented directing effect of the hydroxymethylene group in the selective hypervalent iodine-mediated quinone oxidation. The four synthetic compounds were evaluated for their in vitro cytotoxic activities against six human cancer cells. 8-O-Methylfusarubin was the most potent analogue and displayed excellent cytotoxic activity against MCF-7 breast cancer cells with an IC50 value of 1.01 µM with no cytotoxic effect on noncancerous Vero cells, which could potentially be a promising lead compound for anti-breast cancer drug discovery.
