Design of screen-printed potentiometric platform for sensitive determination of mirabegron in spiked human plasma; molecular docking and transducer optimization.

The integration of molecular modelling simulation and electrochemical sensors is of high interest. Herein, for the first time, a portable solid-contact potentiometric electrode was designed for the sensitive determination of mirabegron (MIR) in human plasma and pharmaceutical formulation. A two-step optimization protocol was investigated for the fabrication of an ion on sensing polymeric membrane. First, molecular docking was used for optimum ionophore selection. Calix[6]arene showed the highest affinity towards MIR with a better docking score (-4.35) and potential energy (-65.23) compared to other calixarene derivatives. Second, carbon nanotubes and gold nanoparticles were investigated as ion-electron transducers using a drop-casting procedure. Gold nanoparticle-based sensors showed better slope, potential stability, and rapid response compared to carbon nanotubes. The proposed solid contact sensors (V-VII) showed comparable sensitivity and ease of handling compared to liquid contact sensors (I-IV). The optimized gold nanoparticles sensor VII produced a Nernstian response over the range of 9.77 × 10-7 to 1 × 10-3 M with LOD of 2.4 × 10-7 M. It has also been used to determine MIR in its pharmaceutical formulation in the presence of a co-formulated antioxidant butylated hydroxytoluene and spiked human plasma. This would offer a feasible and economic platform for monitoring MIR in pharmaceutical preparation and biological fluids.

Design, synthesis, and antitumor efficacy of novel 5-deazaflavin derivatives backed by kinase screening, docking, and ADME studies.

Novel 5-deazaflavins were designed as potential anticancer candidates. Compounds 4j, 4k, 5b, 5i, and 9f demonstrated high cytotoxicity against MCF-7 cell line with IC50 of 0.5-190nM. Compounds 8c and 9g showed preferential activity against Hela cells (IC50: 1.69 and 1.52 µM respectively). However, compound 5d showed notable potency against MCF-7 and Hela cell lines of 0.1 nM and 1.26 µM respectively. Kinase profiling for 4e showed the highest inhibition against a 20 kinase panel. Additionally, ADME prediction studies exhibited that compounds 4j, 5d, 5f, and 9f have drug-likeness criteria to be considered promising antitumor agents deserving of further investigation. SAR study showed that substitutions with 2-benzylidene hydra zino have a better fitting into PTK with enhanced antiproliferative potency. Noteworthy, the incorporation of hydrazino or ethanolamine moieties at position 2 along with small alkyl or phenyl at N-10, respectively revealed an extraordinary potency against MCF-7 cells with IC50 values in the nanomolar range.

HER2 Kinase-Targeted Breast Cancer Therapy: Design, Synthesis, and In Vitro and In Vivo Evaluation of Novel Lapatinib Congeners as Selective and Potent HER2 Inhibitors with Favorable Metabolic Stability.

HER2 kinase as a well-established target for breast cancer (BC) therapy is associated with aggressive clinical outcomes; thus, herein we present structural optimization for HER2-selective targeting. HER2 profiling of the developed derivatives demonstrated potent and selective inhibitions (IC50: 5.4-12 nM) compared to lapatinib (IC50: 95.5 nM). Favorably, 17d exhibited minimum off-target kinase activation. NCI-5-dose screening revealed broad-spectrum activities (GI50: 1.43-2.09 µM) and 17d had a remarkable selectivity toward BC. Our compounds revealed significant selective and potent antiproliferative activities (∼20-fold) against HER2+ (AU565, BT474) compared to HER2(-) cells. At 0.1 IC50, 15i, 17d, and 25b inhibited pERK1/2 and pAkt by immunoblotting. Furthermore, 17d demonstrated potent in vivo tumor regression against the BT474 xenograft model. Notably, a metastasis case was observed in the vehicle but not in the test mice groups. CD-1 mice metabolic stability assay revealed high stability and low intrinsic clearance of 17d (T1/2 > 145 min and CLint(mic) < 9.6 mL/min/kg).