Search Results (5)

Biofilm-associated infections pose significant challenges in healthcare settings due to their resistance to conventional antimicrobial therapies. In the last decade, the marine environment has been a precious source of bioactive molecules, including numerous derivatives with antibiofilm activity. In this study, we reported the synthesis and the biological evaluation of a new series of twenty-two thiadiazopyrimidinone derivatives obtained by using a hybridization approach combining relevant chemical features of two important classes of marine compounds: nortopsentin analogues and Essramycin derivatives. The synthesized compounds were in vitro tested for their ability to inhibit biofilm formation and to disrupt mature biofilm in various bacterial strains. Among the tested compounds, derivative 8j exhibited remarkable dispersal activity against preformed biofilms of relevant Gram-positive and Gram-negative pathogens, as well as towards the fungus Candida albicans, showing BIC₅₀ values ranging from 17 to 40 µg/mL. Furthermore, compound 8j was in vivo assayed for its toxicity and the anti-infective effect in a Galleria mellonella model. The results revealed a promising combination of anti-infective properties and a favorable toxicity profile for the treatment of severe chronic biofilm-mediated infections. Full article

A new series of nortopsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,3,4-oxadiazole or 1,3,4-thiadiazole moiety, was efficiently synthesized. The antiproliferative activity of all synthesized derivatives was evaluated against five pancreatic ductal adenocarcinoma (PDAC) cell lines, a primary culture and a gemcitabine-resistant variant. The five more potent compounds elicited EC₅₀ values in the submicromolar–micromolar range, associated with a significant reduction in cell migration. Moreover, flow cytometric analysis after propidium iodide staining revealed an increase in the G2-M and a decrease in G1-phase, indicating cell cycle arrest, while a specific ELISA demonstrated the inhibition of CDK1 activity, a crucial regulator of cell cycle progression and cancer cell proliferation. Full article

Diverse indoles and bis-indoles extracted from marine sources have been identified as promising anticancer leads. Herein, we designed and synthesized novel bis-indole series 7a–f and 9a–h as Topsentin and Nortopsentin analogs. Our design is based on replacing the heterocyclic spacer in the natural leads by a more flexible hydrazide linker while sparing the two peripheral indole rings. All the synthesized bis-indoles were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. The most potent congeners 7e and 9a against MCF-7 cells (IC₅₀ = 0.44 ± 0.01 and 1.28 ± 0.04 μM, respectively) induced apoptosis in MCF-7 cells (23.7-, and 16.8-fold increase in the total apoptosis percentage) as evident by the externalization of plasma membrane phosphatidylserine detected by Annexin V-FITC/PI assay. This evidence was supported by the Bax/Bcl-2 ratio augmentation (18.65- and 11.1-fold compared to control) with a concomitant increase in the level of caspase-3 (11.7- and 9.5-fold) and p53 (15.4- and 11.75-fold). Both compounds arrested the cell cycle mainly in the G2/M phase. Furthermore, 7e and 9a displayed good selectivity toward tumor cells (S.I. = 38.7 and 18.3), upon testing of their cytotoxicity toward non-tumorigenic breast MCF-10A cells. Finally, compounds 7a, 7b, 7d, 7e, and 9a were examined for their plausible CDK2 inhibitory action. The obtained results (% inhibition range: 16%–58%) unveiled incompetence of the target bis-indoles to inhibit CDK2 significantly. Collectively, these results suggested that herein reported bis-indoles are good lead compounds for further optimization and development as potential efficient anti-breast cancer drugs. Full article

New analogs of nortopsentin, a natural 2,4-bis(3′-indolyl)imidazole alkaloid, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety, and in which a 7-azaindole portion substituted the original indole moiety, were efficiently synthesized. Among all derivatives, prescreened against the HCT-116 colon rectal carcinoma cell line, the two most active compounds were selected and further investigated in different human tumor cells showing IC₅₀ values in the micromolar and submicromolar range. Flow cytometric analysis of propidium iodide-stained MCF-7 cells demonstrated that both the active derivatives caused cell cycle arrest in the G0–G1 phase. The cell death mechanism induced by the compounds was considered to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and observed morphological evaluation using acridine orange/ethidium bromide double staining. Moreover, further tested on intestinal normal-like differentiated Caco-2 cell line, they exhibited preferential toxicity towards cancer cells. Full article

New thiazole nortopsentin analogs in which one of the two indole units was replaced by a naphthyl and/or 7-azaindolyl portion, were conveniently synthesized. Among these, three derivatives showed good antiproliferative activity, in particular against MCF7 cell line, with GI₅₀ values in the micromolar range. Their cytotoxic effect on MCF7 cells was further investigated in order to elucidate their mode of action. Results showed that the three compounds act as pro-apoptotic agents inducing a clear shift of viable cells towards early apoptosis, while not exerting necrotic effects. They also caused cell cycle perturbation with significant decrease in the percentage of cells in the G0/G1 and S phases, accompanied by a concomitant percentage increase of cells in the G2/M phase, and appearance of a subG1-cell population. Full article