Design, Synthesis and Characterisation of Novel Phenothiazine‐Based Triazolopyridine Derivatives: Evaluation of Anti‐Breast Cancer Activity on Human Breast Carcinoma

Abstract

A series of novel phenothiazine based [1,2,4]triazolo[4, 3‐a]pyridine scaffolds were designed and synthesized in good yields by the oxidative cyclisation of phenothiazine pyridylhydrazones. Biological responses of all compounds toward a panel of human breast cancer cells (MDA‐MB‐231, MDA‐MB‐468, MCF7, SKBR3 and T47D) and human non‐tumorigenic epithelial breast cells (MCF10 A) were evaluated. Structure‐activity relationship revealed that compound with pendant phenyl ring on phenothiazine exhibited significant cytotoxic activity and apoptotic induction effects against breast cancer cell line with IC50 value 10.2 to 17.6 μM. Notably, the cytotoxic effect was 3.5 fold higher on cancer than non‐cancer cells, indicating potential control of breast cancer with lower side effects. Molecular docking studies confirmed the presence of hydrophobic contacts between appended phenyl ring, triazolopyridine and phenothiazine moieties with adjacent residues within the binding pocket of tubulin. One of the nitrogen in the triazolo ring also showed hydrogen bonding with tubulin. These tubulin interactions were also found with the taxane ring of paclitaxel. Cell cycle analysis confirmed the G2/M arrest induced by this compound on human breast cancer cells. Therefore, the potential anti‐cancer, pro‐apoptotic, and cell cycle arrest warrant further development of this molecule as a new class of anticancer agent.

Fused Pyridine Derivatives: Synthesis and Biological Activities

“…On the other hand, several triazolopyridine-containing compounds were reported having antibacterial, antiviral, antifungal, antituberculose, and antiparasitic activity [273][274][275][276][277][278]. Additionally, triazolopyridine derivatives were investigated in many studies for their anticancer activity [279][280][281]. Similar to other fused pyridine derivatives, triazolopyridine scaffold has been reported in many papers as kinase inhibitors, such as PIM kinase, JAK1, JAK2, PI3Kgama-delta, ALK-5, VEGFR2 kinase, spleen tyrosine kinase (Syk), c-met kinase, and monopolar spindle 1 (MPS1) kinase inhibitors [282][283][284][285][286][287][288][289][290].…”

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

“…Within the group of compounds prepared, the [ 1 , 2 , 4 ]triazolo[4,3- a ]pyridine bicyclic system was bound to a phenothiazine bearing a phenyl, originating a hybrid (compound 1 , Figure 3 ), which showed considerable apoptosis induction and cytotoxic effect against human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, SKBR3, and T47D), with the percentage of cell viability in the range of 6.2-31.5% at 100 µM. The determined half-maximum inhibitory concentration (IC 50 ) of this new compound against the most affected cancer cell line, MCF-7, was 3.5-fold lower than the obtained inhibitory concentration in non-tumorigenic epithelial breast cells, MCF-10A, which and may indicate a selective effect and thus a reduced risk of side effects [ 21 ]. In this study, the structure-activity relationship (SAR) analysis demonstrated that the phenyl ring linked to the phenothiazine plays a role in cytotoxic activity.…”

“…A molecular docking study of this hybrid compound supported the apoptosis induction effect, being possible to occur a binding to the cavity of tubulin, which can lead to the cell cycle disruption. Interestingly, the triazole ring can interact with the β-tubulin backbone NH of the T276 residue, which also occurs with the oxetane ring of anti-mitotic chemotherapeutic paclitaxel [ 21 , 22 ]. In vitro studies seemed to be in agreement with in silico results, which demonstrated a cell cycle arrest in G2/M and induced apoptosis [ 21 ].…”

“…Interestingly, the triazole ring can interact with the β-tubulin backbone NH of the T276 residue, which also occurs with the oxetane ring of anti-mitotic chemotherapeutic paclitaxel [ 21 , 22 ]. In vitro studies seemed to be in agreement with in silico results, which demonstrated a cell cycle arrest in G2/M and induced apoptosis [ 21 ].…”

Synthesis of Novel Chalcone-Based Phenothiazine Derivatives as Antioxidant and Anticancer Agents

“…In this context, synthesis of the chalcone skeleton, which is present in many natural products with extensive bioactivities [ 11 ], was attempted in conjunction with the phenothiazine core, the first lead pharmacophore of the 20th century [ 12 ]. Several phenothiazine derivatives with various structural motifs have been recently reported and evaluated as anticancer and antioxidant agents [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. For the treatment of Alzheimer’s disease, some N-alkyl and phenothiazine amide derivatives were synthesized, and their efficacy, as well their selectivity as inhibitors for cholinesterase, were investigated [ 22 ].…”