New azolyl-derivatives as multitargeting agents against breast cancer and fungal infections: synthesis, biological evaluation and docking study

Abstract

Nonsteroidal aromatase inhibitors (NSAIs) are well-established drugs for the therapy of breast cancer. However, they display some serious side effects, and their efficacy can be compromised by the development of chemoresistance. Previously, we have reported different indazole-based carbamates and piperidine-sulphonamides as potent aromatase inhibitors. Starting from the most promising compounds, here we have synthesised new indazole and triazole derivatives and evaluated their biological activity as potential dual agents, targeting both the aromatase and the inducible nitric oxide synthase, being this last dysregulated in breast cancer. Furthermore, selected compounds were evaluated as antiproliferative and cytotoxic agents in the MCF-7 cell line. Moreover, considering the therapeutic diversity of azole-based compounds, all the synthesized compounds were also evaluated as antifungals on different Candida strains. A docking study, as well as molecular dynamics simulation, were carried out to shed light on the binding mode of the most interesting compound into the different target enzymes catalytic sites.

Olea europea L. Leaves and Hibiscus sabdariffa L. Petals Extracts: Herbal Mix from Cardiovascular Network Target to Gut Motility Dysfunction Application

“…For the evaluation of NOS inhibition, the L-citrulline assay with fluorimetric detection was followed as previously described [ 22 ]. HPLC analyses were performed using a Waters (Milford, MA, USA) system composed of a P600 model pump, a 2996 photodiode array detector and a 7725i model sample injector (Rheodyne, Cotati, CA, USA).…”

“…Recombinant bovine eNOS was purchased from Cayman Chemical (Ann Arbor, MI, USA). To measure the NOS activity, 10 μL of the test extract solution (100–1 mg/mL) or of the positive control L-NAME (1 mM) was added to the enzyme assay solution [ 22 ], followed by pre-incubation of 15 min at 37 °C. Then, 10 μL of nicotinamide adenine dinucleotide phosphate (NADPH) 7.5 Mm was added to each reaction, and, after 30 min at 37 °C, 500 μL of ice-cold CH 3 CN were added.…”

“…Then, 10 μL of nicotinamide adenine dinucleotide phosphate (NADPH) 7.5 Mm was added to each reaction, and, after 30 min at 37 °C, 500 μL of ice-cold CH 3 CN were added. The mixture was dried under vacuum and then subjected to the L-citrulline fluorescence derivatization [ 22 ]. The content of the L-citrulline was evaluated with respect to the NOS reaction control, where no extract nor inhibitor was added (0% inhibition), whereas L-NAME was the positive control (100% inhibition).…”

Novel imidazole derivatives as potential aromatase and monoamine oxidase-B inhibitors against breast cancer

“…NSAIs are better tolerated than SAIs and do not have severe androgenic side effects. 7 Non-steroidal AI (anastrazole and letrazole) have less side-effect profiles because they are non-covalently bound to the aromatase enzyme and cause reversible inhibition. 8 Heterocyclic rings containing a nitrogen atom play an important role in inhibiting the aromatase enzyme by forming an ionic bond with the iron moiety of hemoglobin (HEM).…”

Design, Synthesis and Biological Evaluation of Aromatase Inhibitors Based on Sulfonates and Sulfonamides of Resveratrol

“…Starting from these premises, we herein surmise that the removal the 3,5-dihydroxy moiety and the anchoring a sulfonamide or sulfonate linker on the 4'-OH of RSV could improve its anticancer activity as well as chemical stability. In our extensive study of new aromatase inhibitors [35,36,[52][53][54], we designed and synthesized a series of 22 analogues of RSV in which the hydroxy groups in 3 and 5 were substituted by hydrogens and the hydroxy group in 4' position was replaced by a sulfonate (1a-k, Figure 3) or a sulfonamide bridge (2a-k, Figure 3) to an aromatic ring, decorated with substituents covering different steric, hydrophobic, electronic and H-bonding properties or to the bioisostere thienyl ring (1k and 2k) or to short alkyl chains (1h-i and 2h-i).…”