3,5-Bis(benzylidene)-4-piperidones and related N-acyl analogs: A novel cluster of antimalarials targeting the liver stage of Plasmodium falciparum

Drug resistance is a major challenge in antimalarial chemotherapy. In addition, a complete cure of malaria requires intervention at various stages in the development of the parasite within the host. There are only a few antimalarials that target the liver stage of the Plasmodium species which is an essential part of the life cycle of the malarial parasite. We report a series of antimalarial 3,5-bis(benzylidene)-4-piperidones and related N-acyl analogs 1–5, a number of which exhibit potent in vitro growth-inhibiting properties towards drug-sensitive D6 and drug-resistant C235 strains of Plasmodium falciparum as well as inhibiting the liver stage development of the malarial life cycle. The compounds 2b (IC₅₀: 165 ng/mL), 3b (IC₅₀: 186 ng/mL), 5c (IC₅₀: 159 ng/mL) and 5d (IC₅₀: 93.5 ng/mL) emerged as lead molecules that inhibit liver stage Plasmodium berghei and are significantly more potent than chloroquine (IC₅₀: >2000 ng/mL) and mefloquine (IC₅₀: >2000 ng/mL) in this screen. All the compounds that showed potent inhibitory activity against the P. berghei liver stage were nontoxic to human HepG2 liver cells (IC₅₀: >2000 ng/mL). The compounds 5a and 5b exhibit comparable metabolic stability as chloroquine and mefloquine in human plasma and the most potent compound 5d demonstrated suitable permeability characteristics using the MDCK monolayer. These results emphasize the value of 3,5-bis(benzylidene)-4-piperidones as novel antimalarials for further drug development.     

Trifluoromethyl-substituted 3,5-bis(arylidene)-4-piperidones as potential anti-hepatoma and anti-inflammation agents by inhibiting NF-кB activation

Some methoxy-, hydroxyl-, pyridyl-, or fluoro-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) could reduce inflammation and promote hepatoma cell apoptosis by inhibiting activation of NF-κB, especially after introduction of trifluoromethyl. Herein, a series of trifluoromethyl-substituted BAPs (4-30) were synthesised and the biological activities were evaluated. We successfully found the most potential 16, which contains three trifluoromethyl substituents and exhibits the best anti-tumour and anti-inflammatory activities. Preliminary mechanism research revealed that 16 could promote HepG2 cell apoptosis in a dose-dependent manner by down-regulating the expression of Bcl-2 and up-regulating the expression of Bax, C-caspase-3. Meanwhile, 16 inhibited activation of NF-κB by directly inhibiting the phosphorylation of p65 and IκBα induced by LPS, together with indirectly inhibiting MAPK pathway, thereby exhibiting both anti-hepatoma and anti-inflammatory activities. Molecular docking confirmed that 16 could bind to the active sites of Bcl-2, p65, and p38 reasonably. The above results suggested that 16 has enormous potential to be developed as a multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.     

Synthesis of (Z)-3-(arylamino)-1-(3-phenylimidazo[1,5-a]pyridin-1-yl)prop-2-en-1-ones as potential cytotoxic agents

The new derivatives based on (Z)-3-(arylamino)-1-(3-phenylimidazo[1,5-a]pyridin-1-yl)prop-2-en-1-one scaffold was synthesized and evaluated for their in vitro cytotoxic potential against a panel of cancer cell lines, viz., A549 (human lung cancer), HCT-116 (human colorectal cancer), B16F10 (murine melanoma cancer), BT-474 (human breast cancer), and MDA-MB-231 (human triple-negative breast cancer). Among them, many of the synthesized compounds exhibited promising cytotoxic potential against the panel of tested cancer cell lines with IC₅₀ <30 µM. Based on the preliminary screening results, the structure-activity relationship (SAR) of the compounds was established. Among the synthesized compounds, 15i displayed a potential anti-proliferative activity against HCT-116 cancer cell line with an IC₅₀ value of 1.21 ± 0.14 µM. Flow cytometric analysis revealed that compound 15i arrested the G0/G1 phase of the cell cycle. Moreover, increased reactive oxygen species (ROS) generation, clonogenic assay, acridine orange staining, DAPI nuclear staining, measurement of mitochondrial membrane potential (ΔΨm), and annexin V-FITC assays revealed that compound 15i promoted cell death through apoptosis.     

Synthesis and in vitro evaluation of 3-(4-nitrophenyl)coumarin derivatives in tumor cell lines

Coumarins are naturally-occurring compounds that have attracted considerable interest due to their numerous biological activities depending on their pattern of substitution on the coumarin molecule. In this present investigation, we synthesized 3-(4-nitrophenyl)coumarin derivatives (9a–e) and evaluated their in vitro cytotoxic effect on human lung (A549), breast (MDA-MB-231) and prostate (PC3) cancer cell lines for 48 h using crystal violet dye binding assay. Cytotoxic effects of the most active compound on normal human lung (MRC-9) and breast (MCF-10A) cell lines, cell cycle analysis using flow cytometry and mitochondrial membrane potential (MMP) using Tetramethyl Rhodamine Methyl Ester (TMRM; rhodamine-123) fluorescent dye were also examined. Among the compounds that were evaluated, 9c showed cytotoxic effect (active), caused significant cells arrest (p < 0.05) in G₀/G₁ and S phases of cell cycle and loss of MMP in A459, MDA-MB-231 and PC3 cell lines. Additionally, the cytotoxic effect of 9c was compared to reference drugs (Coumarin and Docetaxel) for comparative study. These results further demonstrate that acetoxy group at C-7 and C-8 positions of 9c are responsible for the observed cytotoxic effect in these cancer cell lines.     

In-Vitro Cytotoxicity and Cell Cycle Analysis of Two Novel bis-1,2, 4-triazole derivatives: 1,4-bis[5-(5-mercapto-1,3,4-oxadiazol-2-yl-methyl)-thio-4-(p-tolyl)-1,2,4-triazol-3-yl]-butane (MNP-14) and 1,4-bis[5-(carbethoxy-methyl)-thio-4-(p-ethoxy phenyl)-1,2,4-triazol-3-yl]-butane (MNP-16)

In the present study, we have tested the cytotoxic and DNA damage activity of two novel bis-1,2,4 triazole derivatives, namely 1,4-bis[5-(5-mercapto-1,3,4-oxadiazol-2-yl-methyl)-thio-4-(p-tolyl)-1,2,4-triazol-3-yl]-butane (MNP-14) and 1,4-bis[5-(carbethoxy-methyl)-thio-4-(p-ethoxy phenyl) -1,2,4-triazol-3-yl]-butane (MNP-16). The effect of these molecules on cellular apoptosis was also determined. The in-vitro cytotoxicity was evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay as well as Trypan blue dye exclusion methods against human acute lymphoblastic leukemia (MOLT4) and lung cancer cells (A549). Our results showed that MNP-16 induced significant cytotoxicity (IC₅₀ of 3–5 μM) compared with MNP-14. The cytotoxicity induced by MNP-16 was time and concentration dependent. The cell cycle analysis by flow cytometry (fluorescence-activated cell sorting [FACS]) revealed that though there was a significant increase in the apoptotic population (sub-G₁ phase) with an increased concentration of MNP-14 and 16, there was no cell cycle arrest. Further, the comet assay results indicated considerable DNA strand breaks upon exposure to these compounds, thereby suggesting the possible mechanism of cytotoxicity induced by MNP-16. Hence, we have identified a novel molecule (MNP-16) which could be of great clinical relevance in cancer therapeutics.     

Synthesis and characterization of gallium complexes bearing 4-alkyl-2,6-bis(aryliminomethylene)-phenol ligands; crystal structure of dimethyl[4-methyl-2,6-bis-(p-methylphenyliminomethylene)-phenolato]gallium

Eight new dimethylgallium complexes bearing 4-alkyl-2,6-bis(aryliminomethylene)-phenol ligands of type Me₂GaL [L = 4-methyl-2,6-bis-(phenyliminomethylene)-phenolato (3); L = 4-methyl-2,6-bis-(p-methylphenyliminomethylene)-phenolato (4); L = 4-methyl-2,6-bis-(1-naphthyliminomethylene)-phenolato (5); L = 4-methyl-2,6-bis-(2-chlorophenyliminomethylene)-phenolato (6); 4-tert-butyl-2,6-bis-(phenyliminomethylene)-phenolato (7); L = 4-tert-butyl-2,6-bis-(p-methylphenyliminomethylene)-phenolato (8); L = 4-tert-butyl-2,6-bis-(1-naphthyliminomethylene)-phenolato (9); and L = 4-tert-butyl-2,6-bis-(2-chlorophenyliminomethylene)-phenolato] (3) have been synthesized by the reaction of trimethylgallium with appropriate phenol. The complexes obtained have been characterized by elemental analysis, ¹H NMR, IR and mass spectroscopy, respectively. The solid-state structures of dimethyl[4-methyl-2,6-bis-(p-methylphenyliminomethylene)-phenolato]gallium (4) have been determined by X-ray single crystal analysis. In the structure, Ga atom is coordinated by one nitrogen atom and the other nitrogen atom remains constant. The distorted tetrahedron geometry around gallium is presented.     

An in vitro comparative assessment with a series of new triphenyltin(IV) 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates endowed with anticancer activities: structural modifications, analysis of efficacy and cytotoxicity involving human tumor cell lines

Four new triphenyltin(IV) complexes of composition Ph₃SnLH (where LH = 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoate) (1-4) were synthesized and characterized by spectroscopic (¹H, ¹³C and ¹¹⁹Sn NMR, IR, ¹¹⁹Sn Mössbauer) techniques in combination with elemental analysis. The ¹¹⁹Sn NMR spectroscopic data indicate a tetrahedral coordination geometry in non-coordinating solvents. The crystal structures of three complexes, Ph₃SnL¹H (1), Ph₃SnL³H (3), Ph₃SnL⁴H (4), were determined. All display an essentially tetrahedral geometry with angles ranging from 93.50(8) to 124.5(2)°; ¹¹⁹Sn Mössbauer spectral data support this assignment. The cytotoxicity studies were performed with complexes 1-4, along with a previously reported complex (5) in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with the results from other related triphenyltin(IV) complexes (6-7) and tributyltin(IV) complexes (8-11) having 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates framework. In general, the complexes exhibit stronger cytotoxic activity. The results obtained for 1-3 are also comparable to those of its o-analogs i.e. 4-7, except 5, but the advantage is the former set of complexes demonstrated two folds more cytotoxic activity for the cell line MCF-7 with ID₅₀ values in the range 41-53 ng/ml. Undoubtedly, the cytotoxic results of complexes 1-3 are far superior to CDDP, 5-FU and ETO, and related tributyltin(IV) complexes 8-11. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of triphenyltin(IV) complexes 1-7 and tributyltin(IV) complexes 8-11 is also discussed against a panel of human tumor cell lines.     

Molecular basis of the interaction of novel tributyltin(IV) 2/4-[(E)-2-(aryl)-1-diazenyl]benzoates endowed with an improved cytotoxic profile: Synthesis, structure, biological efficacy and QSAR studies

A series of tributyltin(IV) complexes based on 2/4-[(E)-2-(aryl)-1-diazenyl]benzoate ligands was synthesized, wherein the position of the carboxylate and aryl substituents (methyl, tert-butyl and hydroxyl) varies. The complexes, Bu₃SnL^1-4H (1-4), have been structurally characterized by elemental analysis and IR, NMR (¹H, ¹³C, and ¹¹⁹Sn) and ¹¹⁹Sn Mössbauer spectroscopy. All have a tetrahedral geometry in solution and a trigonal bipyramidal geometry in the solid-state, except for Bu₃SnL⁴H (4) that was ascertained to have tetrahedral coordination by X-ray crystallography. Cytotoxicity studies were carried out on human tumor cell lines A498 (renal cancer), EVSA-T (mammary cancer), H226 (non-small-cell lung cancer), IGROV (ovarian cancer), M19 MEL (melanoma), MCF-7 (mammary cancer) and WIDR (colon cancer). Compared to cisplatin, test compounds 1-4 had remarkably good activity, despite the presence of substantial steric bulk due to Sn-Bu ligands. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of organotin(IV) benzoates, along with some reference drug molecules, is also discussed against a panel of human tumor cell lines. Molecular structures of the tributyltin(IV) complexes (1-4) were fully optimized using the PM6 semi-empirical method and docking studies performed with key enzymes associated with the propagation of cancer, namely ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II. The theoretical results are discussed in relation to the mechanistic role of the cytotoxic active test compounds (1-4).     

Biological evaluation of 10-(diphenylmethylene)- 4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives

Antibacterial and antifungal activity of 10-(diphenylmethylene)-4-azatricyclo[5.2.1.0^2,6]dec-8-ene-3,5-dione derivatives were examined by the disc-diffusion method (growth inhibition zone diameter in agar medium). The MIC’s for the most active agents were determined. Title compounds were also evaluated in vitro against representatives of different virus classes. Most of the tested compounds exhibit activity against CVB-2 virus.     

Synthesis and crystal structure of one-dimensional zinc(II) polymer constructed by salicylate and trans-1,2-bis(4-pyridyl)ethylene

A new zinc(II) compound, [Zn₂(Hsal)₄(4,4′-bpe)₂] · [Zn(Hsal)₂(4,4′-bpe)(DMF)(H₂O)] · CH₃OH (1) (Hsal = salicylate and 4,4′-bpe = trans-1,2-bis(4-pyridyl)ethylene) has been synthesized and characterized by elemental analysis, infrared spectroscopy, thermogravimetric analysis, and single crystal X-ray diffraction. The crystal structure consists of three independent moieties: [Zn₂(Hsal)₄(4,4′-bpe)₂], [Zn(Hsal)₂(4,4′-bpe)(DMF)(H₂O)], and non-coordinated CH₃OH molecule. In the compound two independent moieties which are connected by 4,4′-bpe to form 1-D chains, respectively, are further expended to accomplish 2-D network through hydrogen-bonding interactions between non-coordinated methanol and coordinated water molecule or carboxylate oxygen atoms of Hsal ligands.     

Synthesis, spectroscopic properties, X-ray single crystal analysis and antimicrobial activities of organotin(IV) 4-(4-methoxyphenyl)piperazine-1-carbodithioates

A series of mononuclear organotin(IV) complexes of the types, R₃SnL {R = C₄H₉ (1), C₆H₁₁ (2), CH₃ (3) and C₆H₅ (4)}, R₂SnClL {R = C₄H₉ (5), C₂H₅ (7) and CH₃ (9)} and R₂SnL₂ {R = C₄H₉ (6), C₂H₅ (8) and CH₃ (10)}, have been synthesized, where L = 4-(4-methoxyphenyl)piperazine-1-carbodithioate. The ligand-salt and the complexes have been characterized by Raman, FT-IR and multinuclear NMR (¹H, ¹³C and ¹¹⁹Sn) spectroscopy and elemental microanalysis (CHNS). The spectroscopic data substantiate coordination of the ligands to the organotin moieties. The structures of complexes 4 and 6 have been determined by single-crystal X-ray diffraction and illustrate the asymmetric bidentate bonding of the ligand. The packing diagrams indicate O···H and π···H intermolecular interactions in complex 4 and intermolecular S₂C···H interactions in complex 6, resulting in layer structures for both complexes. A subsequent antimicrobial study indicates that the compounds are active biologically and may well be the basis for a new class of fungicides.     

Computational validation of 3-ammonio-3-(4-oxido- 1H-imidazol-1-ium-5-yl) propane-1, 1-bis (olate) as a potent anti-tubercular drug against mt-MetAP

The advent of Multi Drug Resistant (MDR) strain of Mycobacterium tuberculosis (TB) necessitated search for new drug targets for the bacterium. It is reported that 3.3% of all new tuberculosis cases had multidrug resistance (MDR-TB) in 2009 and each year, about 0.44 million MDR-TB cases are estimated to emerge and 0.15 million people with MDR-TB die. Keeping such an alarming situation under consideration we wanted to design suitable anti tubercular molecules for new target using computational tools. In the work Methionine aminopeptidase (MetAP) of Mycobacterium tuberculosis was considered as target and three non-toxic phenolic=ketonic compounds were considered as ligands. Docking was done with Flex X and AutoDock 4.2 separately. Ten proven inhibitors of MetAP were collected from literature with their IC50 and were correlated using EasyQSAR to generate QSAR model. Activity of ligands in question was predicted from QSAR. Pharmacophore for each docking was generated using Ligandscout 3.0. Toxicity of the ligands in question was predicted on Mobyle@rpbs portal and Actelion property explorer. Molecular docking with target showed that of all three ligands, 3-ammonio-3-(4-oxido-1H-imidazol-1-ium-5-yl) propane-1, 1-bis (olate) has highest affinity (- 37.5096) and lowest IC50 (4.46 µM). We therefore, propose that -3-ammonio-3-(4-oxido-1H-imidazol-1-ium-5-yl) propane-1,1- bis(olate) as a potent MetAP inhibitor may be a new anti-tubercular drug particularly in the context of Multi Drug Resistant Tuberculosis (MDR-TB).     

Design and synthesis of novel 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4-thiadiazol- 2-yl)urea derivatives with potent anti-CML activity throughout PI3K/AKT signaling pathway

In this investigation, a series of 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea receptor tyrosine kinase inhibitors were synthesized by a simple and efficient structure-based design. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against human chronic myeloid leukemia (CML) cell line K562, but very weak or no cellular toxicity through monitoring the growth kinetics of K562 cell during a period of 72 h using the real-time live-cell imaging. Among these compounds, 1-(5-((6-((3-morpholinopropyl) amino)pyrimidin-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (7) exhibited the least cellular toxicity and better biological activity in cellular assays (K562, IC₅₀: 0.038 μM). Compound 7 also displayed very good induced-apoptosis effect for human CML cell line K562 and exerted its effect via a significantly reduced protein phosphorylation of PI3K/Akt signal pathway by Human phospho-kinase array analysis. In vitro results indicate that 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea derivatives are lead molecules for further development as treatment of chronic myeloid leukemia and cancer.     

Synthesis, crystal structures, DNA-binding properties, cytotoxic and antioxidation activities of several new ternary copper(II) complexes of N,N′-(p-xylylene)di-alanine acid and 1,10-phenanthroline

Three novel ternary copper(II) complexes, [Cu₂(phen)₂(l-PDIAla)(H₂O)₂](ClO₄)₂·2.5H₂O (1), [Cu₄(phen)₆(d,l-PDIAla)(H₂O)₂](ClO₄)₆·3H₂O (2) and [Cu₂(phen)₂(d,l-PDIAla)(H₂O)](ClO₄)₂·0.5H₂O (3) (phen = 1,10-phenanthroline, H₂PDIAla = N,N’-(p-xylylene)di-alanine acid) have been synthesized and structurally characterized by single-crystal X-ray crystallography and other structural analysis. Spectrometric titrations, ethidium bromide displacement experiments, CD (circular dichroism) spectral analysis and viscosity measurements indicate that the three compounds, especially the complex 3, strongly bind to calf-thymus DNA (CT-DNA). The intrinsic binding constants of the ternary copper(II) complexes with CT-DNA are 0.89 × 10⁵, 1.14 × 10⁵ and 1.72 × 10⁵ M⁻¹, for 1, 2 and 3, respectively. Comparative cytotoxic activities of the copper(II) complexes are also determined by acid phosphatase assay. The results show that the ternary copper(II) complexes have significant cytotoxic activity against the HeLa (Cervical cancer), HepG2 (hepatocarcinoma), HL-60 cells (myeloid leukemia), A-549 cells (pulmonary carcinoma) and L02 (liver cells). Investigations of antioxidation properties show that all the copper(II) complexes have strong scavenging effects for hydroxyl radicals and superoxide radicals.     

Ruthenium(II/III) mediated transformation of 1,2-bis(2′-pyridylmethyleneimino)benzene (L) to 2-(2′-benzimidazolyl)pyridine (L′H) and its in situ formed complexes with Ru(II): X-ray structure of trans-[Ru(PPh3)2(L′H)2](ClO4)2

A series of ruthenium (II) complexes of formulae trans-[Ru(PPh₃)₂(L′H)₂](ClO₄)₂ (1), [Ru(bpy)(L′H)₂](ClO₄)₂ (2), [Ru(bpy)₂(L′H)](ClO₄)₂ (3), cis-[Ru(DMSO)₂(L′H)₂]Cl₂ (4), and [Ru(L′H)₃](PF₆)₂ (5) (where L′H = 2-(2′-benzimidazolyl)pyridine) have been synthesized by reaction of the appropriate ruthenium precursor with 1,2-bis(2′-pyridylmethyleneimino)benzene (L). The complexes were characterized by elemental analyses, spectroscopic and electrochemical data. All the complexes were found to be diamagnetic and hence metal is in +2 oxidation state. The molecular structure of trans-[Ru(PPh₃)₂(L′H)₂](ClO₄)₂ has been determined by the single crystal X-ray diffraction studies. The molecular structure shows that Ru(II) is at the center of inversion of an octahedron with N₄P₂ coordination sphere. The ligand acts as a bidentate N,N′donor. The electronic spectra of the complexes display intense MLCT bands in the visible region.Cyclic voltammetric studies show quasi-reversible oxidative response at 0.99-1.32 V (vs Ag/AgCl reference electrode) due to Ru(III)/Ru(II) couple.     

Synthesis,Antifungal Activity,DFT Study and Molecular Dynamics Simulation of Novel 4-(1,2,4-Oxadiazol-3-yl)-N-(4-phenoxyphenyl)benzamide Derivatives

In order to find novel potential antifungal agrochemicals, a series of new 4-(1,2,4-oxadiazol-3-yl)-N-(4-phenoxyphenyl)benzamide derivatives 3a – j were designed, synthesized and characterized by their ¹H - , ¹³C-NMR and HRMS spectra. The preliminary antifungal assay in vitro revealed that compounds 3a – j exhibited moderate to good antifungal activity against five plant pathogenic fungi. Especially, compound 3e presented significant antifungal activity against Alternaria solani, Botrytis cinerea and Sclerotinia sclerotiorum, superior to positive control boscalid. In the in vivo antifungal assay on tomato plants and cucumber leaves, compound 3e presented good inhibition rate against B. cinerea at 200 mg/L. Molecular dynamics simulation revealed that compound 3e could bind with the active site of class II histone deacetylase (HDAC).     

3-[2-Amino-2-imidazolin-4(5)-yl]alanine (enduracididine) and 2-[2-amino-2-imidazolin-4(5)-yl] acetic acid in seeds of Lonchocarpus sericeus

3-[2-Amino-2-imidazolin-4(5)-yl]alanine (enduracididine) and 2-[2-amino-2-imidazolin-4(5)-yl] acetic acid have been isolated from seeds of Lonchocarpus sericeus. The concentration of each compound was ca 0.5 % of the fresh seed weight.     

Discovery of 2-ethoxy-4-(methoxymethyl)benzamide derivatives as potent and selective PTP1B inhibitors

Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, is considered as a promising and validated therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. Upon careful study, a series of 2-ethoxy-4-(methoxymethyl)benzamide and 2-ethoxy-5-(methoxymethyl)benzamide analogs designed by the “bioisosteric principle” were discovered, wherein their PTP1B inhibitory potency, type of PTP1B inhibition, selectivity and membrane permeability were evaluated. Among them, compound 10m exhibited high inhibitory activity (IC₅₀ = 0.07 μM), significant selectivity (32-fold) over T-cell PTPase (TCPTP) as well as good membrane permeability (P_app = 2.41 × 10⁻⁶ cm/s). Further studies on cell viability and cellular activity revealed that compound 10m could enhance insulin-stimulated glucose uptake with no significant cytotoxicity.