Background: Carbazole-based molecules containing thiosemicarbazide functional groups are recognized for their diverse biological activities, particularly in enhancing therapeutic anticancer effects through inhibiting crucial pathways. These derivatives also exhibit noteworthy antioxidant properties. Objectives: This study aims to synthesize, characterize, and evaluate the antioxidant and anticancer activities of 18 novel carbazole derivatives. Methods: The radical scavenging capabilities of the compounds were assessed using the 2,2-diphenyl-1-picrylhydrazyl assay. Antiproliferative activities were evaluated on MCF-7 cancer cell lines through viability assays. Additionally, the modulation of the PI3K/Akt/mTOR pathway, apoptosis/necrosis induction, and cell cycle analysis were conducted for the most promising anticancer agents. Results: nine compounds showed potent antioxidant activities with IC₅₀ values lower than the positive control acarbose, with compounds 4 h and 4y exhibiting the highest potency (IC₅₀ values of 0.73 and 0.38 µM, respectively). Furthermore, compounds 4o and 4r displayed significant anticancer effects, with IC₅₀ values of 2.02 and 4.99 µM, respectively. Compound 4o, in particular, exhibited promising activity by targeting the PI3K/Akt/mTOR signaling pathway, inhibiting tumor survival, inducing apoptosis, and causing cell cycle arrest in MCF-7 cell lines. Furthermore, compound 4o was showed significant antimicrobial activities against S. aureus and E. coli, and antifungal effect against C. albicans. Its potential to overcome drug resistance through this pathway inhibition highlights its promise as an anticancer agent. Molecular docking simulations supported these findings, revealing favorable binding profiles and interactions within the active sites of the enzymes PI3K, AKT1, and mTOR. Moreover, assessing the druggability of the newly synthesized thiosemicarbazide derivatives demonstrated optimal physicochemical properties, further endorsing their potential as drug candidates.

Background: The carbazole skeleton is an important structural motif occurring naturally or synthesized chemically and has antihistaminic, antioxidant, antitumor, antimicrobial, and anti-inflammatory activities.Objectives: This study aimed to design and synthesize a novel series of carbazole derivatives and evaluate their antiproliferative and antioxidant activities.Methods: The synthesized compounds were characterized utilizing HRMS,¹H-, and¹³C_APT-NMR, and assessed for their anticancer, antifibrotic, and antioxidant effects utilizing reference biomedical procedures. In addition, the AutoDock Vina application was used to perform in-silico docking computations.Results: A series of carbazole derivatives were synthesized and characterized in the current study. Compounds10and11were found to have a stronger antiproliferative effect than compounds2–5against HepG2, HeLa, and MCF7 cancer cell lines with IC₅₀values of 7.68, 10.09, and 6.44 µM, respectively. Moreover, compound 9 showed potent antiproliferative activity against HeLa cancer cell lines with an IC₅₀value of 7.59 µM. However, except for compound5, all of the synthesized compounds showed moderate antiproliferative activities against CaCo-2 with IC₅₀values in the range of 43.7–187.23 µM. All of these values were compared with the positive control anticancer drug 5-Fluorouracil (5-FU). In addition, compound9showed the most potent anti-fibrotic compound, and the cellular viability of LX-2 was found 57.96% at 1 µM concentration in comparison with the positive control 5-FU. Moreover, 4 and 9 compounds showed potent antioxidant activities with IC₅₀values of 1.05 ± 0.77 and 5.15 ± 1.01 µM, respectively.Conclusion: Most of the synthesized carbazole derivatives showed promising antiproliferative, antioxidant, and antifibrotic biological effects, and further in-vivo investigations are needed to approve or disapprove these results.

A novel series of pyrrole-3-one derivatives were synthesized using furan-3-one derivatives and various aromatic amines. The synthesized compounds were identified by spectral studies such as IR, NMR and HRMS. Dielectric properties of the target compounds were experimentally determined by dielectric spectroscopy in the frequency range of 20 Hz − 1 MHz. The real part of the dielectric constant, dielectric loss tangent and conductivity of the samples were investigated as a function of applied frequency. Dielectric measurements showed Ata7 has the maximum dielectric constant at 1 kHz, while Ata1 has a negative dielectric constant value. When the result is evaluated with theoretical calculations, grain boundaries play an effective role in the experimental observed dielectric constant. Additionally, in this research the pyrrole-3-one derivatives (Ata1-9) were theoretically optimized and over these structures, NMR with GIAO (gauge-independent atomic orbital), UV with TD (time dependent), frontier orbitals (HOMO and LUMO), NLO (nonlinear optical properties) and MEP (molecular electrostatic potential) analysis were carried out. Quantum chemical computations were performed by Density Functional Theory (DFT) using B3LYP functional and 6-311++G (d,p) basis set. Later, the molecular docking analysis between Ata1-9 and two different receptors such as 3RZE and 3TDA was performed using AutoDock Vina program. Lastly, drug-likeness, physicochemical and ADME/T properties of the designed compounds were computed with the help of SwissADME online tool. Communicated by Ramaswamy H. Sarma

Currently, available therapies for diabetes cannot achieve normal sugar values in a high percentage of treated patients. This work synthesized a series of carbazole-triazole-thione derivatives, and their potential antidiabetic activity was investigated against the key diabetic enzymes α-amylase and glycosidase. Normal human hepatic stellate cells (LX-2) were employed to assess their cytotoxicity and safety, followed by in vivo testing to investigate the hypoglycemic effect of the most promising agent. As a result, a set of 18 carbazole-1,2,4-triazole-thione derivatives were synthesized. Seven structures demonstrated potential inhibitory activity against α-amylase enzyme, with IC₅₀ lower than 6.4 μM. Among them, compounds C5f, C5o, and C5r exhibited the highest potency, with IC₅₀ values of 0.56, 0.53, and 0.97 μM, respectively, compared to the well-known α-amylase inhibitor acarbose, which has an IC₅₀ value of 5.31 μM. Exploring the inhibition potency of these series against α-glucosidase enzyme revealed that C5f and C5r compounds act as moderate inhibitors, with IC₅₀ values of 11.03 and 13.76 μM, respectively. Moreover, at 100 μM concentration, most of the evaluated compounds showed negligible cytotoxic effect against LX-2 cell lines, particularly compounds C5o and C5s, that demonstrated lower cytotoxic activity by 3-fold compared to the positive control 5-Flururicle (cell viability 13.45%). Thus, the C5f compound was selected for in vivo evaluation, and after administering five doses of this compound (10 mg/kg) to group III of mice, a significant reduction in glucose concentration was observed, bringing it down from 290.54 to 216.15 mg/dL, in comparison with the control group which did not show a reduction in blood glucose level. These observed in vitro and in vivo results were upheld by performing a set of chemoinformatic studies that elucidated the binding interactions of the most active derivatives within the enzyme's active site and highlighted the critical roles of both the 1,2,4-triazole-3-thione and carbazole scaffolds in these interactions. Finally, the drug-likeness profiles of our carbazole-triazole-thione derivatives suggest their potential as candidates for further in vivo studies and clinical trials.