5-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid

In the mol­ecule of the title compound, C10H9N3O2, the pyrazole ring is approximately coplanar with the amino and carboxyl groups. The phenyl group is twisted by 48.13 (3)° relative to this plane. An intra­molecular N—H⋯O hydrogen bond stabilizes the planar conformation of the mol­ecule. The mol­ecules are linked into two-dimensional sheets by two strong inter­molecular N—H⋯N and O—H⋯O hydrogen bonds. The latter forms the classic carboxylic acid dimer motif

Discovery and prospects of new heterocyclic Isatin-hydrazide derivative with a novel role as estrogen receptor α degrader in breast cancer cells

Introduction: Isatin, a heterocycle scaffold, is the backbone of many anticancer drugs and has previously been reported to engage multiple cellular targets and mechanisms, including angiogenesis, cell cycle, checkpoint pathways and multiple kinases. Here, we report that a novel isatin derivative, 5i, degrades estrogen receptor alpha (ERα) in estrogen-dependent breast cancer cells. This effect of the isatin nucleus has not been previously reported. Tamoxifen and fulvestrant represent standard therapy options in estrogen-mediated disease but have their own limitations. Isatin-based triple angiokinase inhibitor BIBF1120 (Nintedanib) and multikinase inhibitor Sunitinib (Sutent) have been approved by the FDA.Methods: Keeping this in view, we synthesized a series of N'-(1-benzyl-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) hydrazide derivatives and evaluated them in vitro for antiproliferative activities in MCF-7 (ER+) cell line. We further investigated the effect of the most potent compound (5i) on the Erα through Western Blot Analysis. We used in silico pharmacokinetics prediction tools, particularly pkCSM tool, to assess the activity profiles of the compounds.Results and discussion: Compound 5i showed the best antiproliferative activity (IC50 value; 9.29 ± 0.97 µM) in these cells. Furthermore, 5i downregulated ERα protein levels in a dose-dependent manner in MCF-7. A multifaceted analysis of physicochemical properties through Data Warrior software revealed some prominent drug-like features of the synthesized compounds. The docking studies predicted the binding of ligands (compounds) with the target protein (ERα). Finally, molecular dynamics (MD) simulations indicated stable behavior of the protein-ligand complex between ERα and its ligand 5i. Overall, these results suggest that the new isatin derivative 5i holds promise as a new ERα degrader

A Comprehensive Review of Aminochalcones

Chalcones, members of the flavonoid family, display a plethora of interesting biological activities including but not limited to antioxidant, anticancer, antimicrobial, anti-inflammatory, and antiprotozoal activities. The literature cites the synthesis and activity of a range of natural, semisynthetic, and synthetic chalcones. The current review comprehensively covers the literature on amino-substituted chalcones and includes chalcones with amino-groups at various positions on the aromatic rings as well as those with amino-groups containing mono alkylation, dialkylation, alkenylation, acylation, and sulfonylation. The aminochalcones are categorized according to their structure, and the corresponding biological activities are discussed as well. Some compounds showed high potency against cancer cells, microbes, and malaria, whereas others did not. The purpose of this review is to serve as a one-stop location for information on the aminochalcones reported in the literature in recent years

A cell-based high-throughput screen identifies inhibitors that overcome P-glycoprotein (Pgp)-mediated multidrug resistance.

Multidrug resistance (MDR) to chemotherapeutic drugs remains one of the major impediments to the treatment of cancer. Discovery and development of drugs that can prevent and reverse the acquisition of multidrug resistance constitute a foremost challenge in cancer therapeutics. In this work, we screened a library of 1,127 compounds with known targets for their ability to overcome Pgp-mediated multidrug resistance in cancer cell lines. We identified four compounds (CHIR-124, Elesclomol, Tyrphostin-9 and Brefeldin A) that inhibited the growth of two pairs of parental and Pgp-overexpressing multidrug-resistant cell lines with similar potency irrespective of their Pgp status. Mechanistically, CHIR-124 (a potent inhibitor of Chk1 kinase) inhibited Pgp activity in both multidrug-resistant cell lines (KB-V1 and A2780-Pac-Res) as determined through cell-based Pgp-efflux assays. Other three inhibitors on the contrary, were effective in Pgp-overexpressing resistant cells without increasing the cellular accumulation of a Pgp substrate, indicating that they overcome resistance by avoiding efflux through Pgp. None of these compounds modulated the expression of Pgp in resistant cell lines. PIK-75, a PI3 Kinase inhibitor, was also determined to inhibit Pgp activity, despite being equally potent in only one of the two pairs of resistant and parental cell lines. Strong binding of both CHIR-124 and PIK-75 to Pgp was predicted through docking studies and both compounds inhibited Pgp in a biochemical assay. The inhibition of Pgp causes accumulation of these compounds in the cells where they can modulate the function of their target proteins and thereby inhibit cell proliferation. In conclusion, we have identified compounds with various cellular targets that overcome multidrug resistance in Pgp-overexpressing cell lines through mechanisms that include Pgp inhibition and efflux evasion. These compounds, therefore, can avoid challenges associated with the co-administration of Pgp inhibitors with chemotherapeutic or targeted drugs such as additive toxicities and differing pharmacokinetic properties

Functionalization of surfactant templated magnetite by chitosan and PEGylated/Chitosan – In vitro studies on drug loading, release and anti-proliferative activity

Magnetite iron oxide nanoparticles (MNPs) were synthesized using micro emulsion assisted co-precipitation method. The surface functionalization of MNPs was done with chitosan and PEGylated/chitosan and three samples of each were prepared. These materials were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron (SEM), and transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). The Methotrexate (MTX) drug was then loaded on each functionalized MNPs as MCT-1–3 (chitosan; 0.1,0.5, and 1%) and MPCT-1–3 (PEGylated/chitosan (1% each with volume ratio 1:1, 3:1, and 1:3). Each composition showed maximum encapsulation efficiency (>95%). The pH dependent drug release studies were done under acidic (pH 5.0) and physiological (pH 7.4) conditions. These studies revealed consistent drug release and no burst release was observed from both functionalized MNPs. A comparatively delayed release from MPCTs than MCTs could be attributed to the formation of more compact sphere due to cross-linking of chitosan with PEG. The drug release was found greater at pH 5.0 for all functionalized MNPs. However, among all functionalized MNPs, maximum drug release was found to be 78.88% by MPCT-1 in acidic medium (pH 5.0). Cyclic voltametric (CV) analysis at slow scan rate (10 mV/s) further indicated controlled drug release and complimented the UV-findings. The MCF-7 (human breast cancer) cell line studies, however, indicated anticancer potential only for MPCT-1–3 with IC50 values ranging from 1.4 to 1.7 μM. Overall results pointed that methotrexate loaded PEGylated/chitosan coated magnetic nanoparticles MPCT-1 is the more compassionate material to be used as vehicle for controlled drug delivery

Plants as a Promising Reservoir of Tyrosinase Inhibitors

The process of melanogenesis, that takes place in the melanocytes of the epidermis, leads to hyperpigmentation. The biosynthetic pathway for production of melanin involves the enzyme tyrosinase that has been an attractive target for cosmaceutical research. Numerous synthetic, semisynthetic and natural, especially plant-based, inhibitors of tyrosinase have been reported in the literature. In plants, the secondary metabolites like flavonoids, chalcones, stilbenes, tannins, hydroquinone and kojic acid, etc... have been shown to possess the anti-tyrosinase activity. In the current review, we have covered the progress in this sphere that would be useful for not only further mechanistic investigations but also for the optimization of the structure of the metabolites for improved activity and selectivity. Thus the review presents a comprehensive report on tyrosinase inhibitors of plant origin reported in the extract form or as isolated compounds. Huge gap has been found between research and industry due to inconsistent pursual of the potent plant based extracts. There is a need to completely evaluate the extracts for structure optimization using molecular docking and evaluation of the safety inorder to benefit the industry with non toxic biological friendly products through invivo and exvivo optimization

Surface plasmon resonance-based synthesis of gold nanorods for sensing applications

Gold nanomaterials possess leading interest in the field of nanomaterials due to their vast applications both in advanced chemical and medicinal industries. Gold nanorods (AuNRs) were synthesized via a seed-mediated growth approach for catalytic and electrocatalytic applications. UV–vis absorption spectroscopy and scanning electron microscopy were employed to characterize AuNRs. The focus was to achieve AuNRs of high aspect ratios and good yield. For anisotropic AuNRs, two plasmon peaks are observed; transverse and longitudinal peaks. In the synthesis process, morphology of the gold nanorods was tuned varying the pH of the solution ranges from 3.45 to 1.6. By varying the pH, gold nanorods of different aspect ratios were obtained. Gold nanorods with the aspect ratio of 7.5 containing maximum amount of nitric acid and a pH value of 1.6 revealed the most stability. Catalytic applications were monitored by degradation of an organic pollutant. The degradation percentages of 98% were achieved at 12 min duration. Non-enzymatic electrochemical glucose sensor was fabricated via glassy carbon electrode modification with gold nanorods and studied using cyclic voltammetry. All samples showed good electrochemical response. Among all samples, the one with maximum amount of nitric acid and a pH value of 1.6 revealed the most stability and high sensitivity for glucose sensing. Graphical abstract: [Figure not available: see fulltext.]

Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C–H Borylation and Suzuki Coupling

A convenient two-step preparation of NH-free 5-aryl-pyrrole-2-carboxylates is described. The synthetic route consists of catalytic borylation of commercially available pyrrole-2-carboxylate ester followed by Suzuki coupling without going through pyrrole N–H protection and deprotection steps. The resulting 5-aryl substituted pyrrole-2-carboxylates were synthesized in good- to excellent yields. This synthetic route can tolerate a variety of functional groups including those with acidic protons on the aryl bromide coupling partner. This methodology is also applicable for cross-coupling with heteroaryl bromides to yield pyrrole-thiophene, pyrrole-pyridine, and 2,3’-bi-pyrrole based bi-heteroaryls