Design, synthesis, in silico molecular docking, and ADMET studies of quinoxaline-isoxazole-piperazine conjugates as EGFR-targeting agents.

In this paper, we report the synthesis of quinoxaline-isoxazole-piperazine conjugates. The anticancer activity was evaluated against three human cancer cell lines, including MCF-7 (breast), HepG-2 (liver), and HCT-116 (colorectal). The outcomes of the tested compounds 5d, 5e, and 5f have shown more potent activity when compared to the standard drug erlotinib. In a cell survivability test (MCF-10A), three potent compounds (5d, 5e, and 5f) were evaluated against the normal breast cell line, although neither of them displayed any significant cytotoxicity with IC50 values greater than 84 µM. Furthermore, the compounds 5d, 5e, and 5f were tested for tyrosine kinase EGFR inhibitory action using erlotinib as the reference drug and compound 5e was shown to be more potent in inhibiting the tyrosine kinase EGFR than sorafenib. In addition to this, molecular docking studies of compounds 5d, 5e, and 5f demonstrated that these compounds had more EGFR-binding interactions. The potent compounds 5d, 5e, and 5f were subjected to in silico pharmacokinetic assessment by SWISS, ADME, and pkCSM. While the compounds 5d, 5e, and 5f followed Lipinski, Veber, Egan, and Muegge rules without any deviation.

Study of the ß-oxygen effect in the Barton-McCombie reaction for the total synthesis of (4R,5R)-4-hydroxy-γ-decalactone (Japanese orange fly lactone): a carbohydrate based approach.

Efficient and facile synthesis of Japanese orange fly lactone (1) was achieved from a commercially available d-glucose by investigating the Barton-McCombie reaction with furanose anomeric isomers (12α , ß) with an overall yield of 12.6%. During the course of this synthesis, the ß-oxygen effect was discovered in the deoxygenation step at the C-3 position using the Barton-McCombie reaction, where the substrate allows the effect to operate in one of the isomers but not in the other. Under the same reaction conditions, xanthate derived from the ß-furanose isomer affords a high yield of deoxygenated product, whereas the α-isomer produces a very low yield. The key transformations used were Wittig olefination, TEMPO mediated oxidation, and Barton-McCombie deoxygenation, resulting in a concise total synthesis of Japanese orange fly lactone (1). Our success will allow for further biological studies of this natural product, as well as opportunities for developing new potentially promising pheromones.

Design, Synthesis, and Molecular Docking Studies of Some New Quinoxaline Derivatives as EGFR Targeting Agents.

The synthesis of some new quinoxaline derivatives (IVa-n) and their structure determination using 1H NMR, 13C NMR and mass spectral analysis was described herein. The in vitro anti-cancer activity of the these compounds (IVa-n) revealed that the compound1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5-a]quinoxalin-4-yl)pyrazolidine-3,5-dione (IVd) has shown promising activity, whereas, compounds 1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5-a]quinoxalin-4-yl)pyrazolidine-3,5-dione (IVa), 1-(tetrazolo[1,5-a]quinoxalin-4-yl)-2-((1-(m-tolyl)-1H-1,2,3-triazol-4-yl)methyl)pyrazolidine-3,5-dione (IVb), 1-((1-(3,5-dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5-a]quinoxalin-4-yl)pyrazolidine-3,5-dione (IVh) and 1-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5-a]quinoxalin-4-yl)pyrazolidine-3,5-dione (IVi) exhibited good to moderate activity against four human cancer cell lines such as HeLa, MCF-7, HEK 293T, and A549 as compared to the doxorubicin. Predominantly, the compound displayed excellent activity over HeLa, MCF-7, HEK 293T, and A549 with IC50 values of 3.20 ± 1.32, 4.19 ± 1.87, 3.59 ± 1.34, and 5.29 ± 1.34 µM, respectively. Moreover, molecular docking studies of derivatives (IVa-n) on EGFR receptor suggested that the most potent compound strongly binds to protein EGFR (pdbid:4HJO) and the energy calculations of in silico studies were also in good agreement with the obtained IC50 values. Supplementary Information: The online version contains supplementary material available at 10.1134/S1068162022030220.

Fused benzo[1,3]thiazine-1,2,3-triazole hybrids: Microwave-assisted one-pot synthesis, in vitro antibacterial, antibiofilm, and in silico ADME studies.

In this paper, we report an efficient one-pot three-component reaction sequences comprising Cu(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) followed by Cu-catalyzed arylation of resulting 1,2,3-triazole in the presence of ionic liquid [Emim]BF4 under microwave conditions involving. The newly synthesized derivatives were screened for in vitro antibacterial inhibition potency against both gram +ve and gram -ve strains. Among the tested compounds, 4f exhibited significant inhibition activity with MIC value 3.12 µg/mL against B. subtilis and S. epidermidis which is two-fold higher than the standard ciprofloxacin (6.25 µg/mL) and also displayed equipotent activity to that of the positive control against S. aureus with MIC value 6.25 µg/mL. Conjugates of the series viz. 3f and 4b against S. aureus, and 4e against E. coli have also displayed promising results with MIC values 6.25 µg/mL which is comparable to the ciprofloxacin. Also we report the anti-biofilm profiles for the potent compounds and it was observed from the results that the active derivatives 4b and 4f were not only potent antibacterial agents but also efficient inhibitors of B. subtilis and S. aureus biofilm growth. Furthermore, in silico-ADME and pharmacokinetic profiles demonstrated the druggability of the hybrids.