Pongsit Vijitphan

This study is the first to fully synthesize oxostephanine (1) and thailandine (2), two aporphine alkaloids that were originally found in Stephania venosa (Blume) Spreng. The synthesis described in this study utilized commercially available starting materials, namely 2‐bromo‐6‐methoxybenzaldehyde and 3,4‐dihydroxybenzaldehyde. The B‐ring moiety of aporphines was successfully synthesized through the utilization of the Bischler‐Napieralski cyclization process. The synthesis of the C ring in oxoaporphine was accomplished using an order of crucial steps, namely biaryl coupling, incorporation of trifluoroacetyl‐containing scaffolds, and palladium coupling, followed by oxidation using Fremy's salt. The synthesis of oxostephanine (1) and thailandine (2) was successfully achieved in 11 and 12 steps, respectively, resulting in equivalent overall yields of 11.7 %. This study aimed to increase amount of interested compounds and explore the biological activity of those compounds. In this study, both compounds were subjected to testing for antibacterial activity using the CLSI standard M100 guideline. Oxostephanine (1) has shown significant antibacterial efficacy against gram‐positive bacteria and bacterial biofilms, as seen by minimum inhibitory concentration (MIC) values ranging from 7.8 to 125 μg/mL. Conversely, higher MIC values of 250 μg/mL indicated that thailandine (2) exhibited limited antimicrobial activity.

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.

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 (M^pro) 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 (M^pro), 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 M^pro ranged from −7.06 to −10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to M^pro 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.

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-(5″-cyanopyridin-2″ylamino)quinoline (6b) and 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino)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.