Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent.

Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides (SSE1901-SSE1932) and the evaluation of their antiproliferative activities. N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917) exhibited the most potent activity with GI50 values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells. SSE1917 stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G2/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore, SSE1917 suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.

Ugi Bis-Amide Derivatives as Tyrosinase Inhibitor; Synthesis, Biology Assessment, and in Silico Analysis.

Herein, a straightforward synthetic strategy mediated by Ugi reaction was developed to synthesize novel series of compounds as tyrosinase inhibitors. The structures of all compounds were confirmed by FT-IR, 1 H-NMR, 13 C-NMR, and CHNOS techniques. The tyrosinase inhibitory activities of all synthesized derivatives 5a-m were determined against mushroom tyrosinase and it was found that derivative 5c possesses the best inhibition with an IC50 value of 69.53±0.042 µM compared to the rest of the synthesized derivatives. Structure-activity relationships (SARs) showed that the presence of 4-MeO or 4-NO2 at the R2 position plays a key role in tyrosinase inhibitory activities. The enzyme kinetics studies showed that compound 5c is an noncompetitive inhibitor. For in silico study, the allosteric site detection was first applied to find the appropriate binding site and then molecular docking and molecular dynamic studies were performed to reveal the position and interactions of 5c as the most potent inhibitor within the tyrosinase active site. The results showed that 5c bind well with the proposed binding site and formed a stable complex with the target protein.

Amide- and bis-amide-linked highly potent and broadly active antifungal agents for the treatment of invasive fungal infections- towards the discovery of pre-clinical development candidate FC12406.

Most fungal infections are common, localized to skin or mucosal surfaces and can be treated effectively with topical antifungal agents. However, while invasive fungal infections (IFIs) are uncommon, they are very difficult to control medically, and are associated with high mortality rates. We have previously described highly potent bis-guanidine-containing heteroaryl-linked antifungal agents, and were interested in expanding the range of agents to novel series so as to reduce the degree of aromaticity (with a view to making the compounds more drug-like), and provide broadly active high potency derivatives. We have investigated the replacement of the central aryl ring from our original series by both amide and a bis-amide moieties, and have found particular structure-activity relationships (SAR) for both series', resulting in highly active antifungal agents against both mold and yeast pathogens. In particular, we describe the in vitro antifungal activity, absorption, distribution, metabolism and elimination (ADME) properties, and off-target properties of FC12406 (34), which was selected as a pre-clinical development candidate.

Discovery of novel 2-aryl-4-bis-amide imidazoles (ABAI) as anti-inflammatory agents for the treatment of inflammatory bowel diseases (IBD).

A series of 2-Aryl-4-Bis-amide Imidazoles (ABAI-1 to 30) were designed as anti-inflammatory agents. These compounds were synthesized and evaluated for the in vitro anti-inflammatory activities (inhibition of NO production and release of inflammatory cytokines). Several compounds effectively inhibited NO production in lipopolysaccharide (LPS) induced RAW264.7 cells. Among them, ABAI-30 exhibited the highest NO-inhibitory effect (inhibition rate of 87% at 20 µM). The anti-inflammatory mechanism of ABAI-30 was examined and found to be inhibiting the TLR4-pp65 and NLRP3-caspase-1 signaling pathway, thus leading to the downregulation of IL6, IL-1ß and TNFα at both transcriptional and translational levels. Importantly, ABAI-30 demonstrated high in vivo anti-inflammatory efficacy in a dextran sulfate sodium (DSS)-induced colitis mouse model without causing obvious toxicity. Collectively, our study provides a potent anti-inflammatory agent, which deserves further investigation as a novel therapeutic candidate for treating inflammatory bowel diseases.

Synthesis, Crystal Structures and Properties of Ferrocenyl Bis-Amide Derivatives Yielded via the Ugi Four-Component Reaction.

Ten ferrocenyl bis-amide derivatives were successfully synthesized via the Ugi four-component reaction by treating ferrocenecarboxylic acid with diverse aldehydes, amines, and isocyanides in methanol solution. Their chemical structures were fully characterized by IR, NMR, HR-MS, and X-ray diffraction analyses. They feature unique molecular morphologies and create a 14-membered ring motif in the centro-symmetric dimers generated in the solid state. Moreover, the electrochemical behavior of these ferrocenyl bis-amides was assessed by cyclic voltammetry.

Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold.

TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK-3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC50=16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.

Enhanced crystallization, heat resistance and transparency of poly(lactic acid) with self-assembling bis-amide nucleator.

The application of poly(lactic acid) (PLA) is limited by its low crystallization rate. Conventional methods to increase crystallization rate usually result in a significant loss of transparency. In this work, a bundled bis-amide organic compound N'-(3-(hydrazinyloxy)benzoyl)-1-naphthohydrazide (HBNA) was used as a nucleator to prepare PLA/HBNA blends with enhanced crystallization, heat resistance and transparency. HBNA dissolves in PLA matrix at high temperature and self-assembles into bundle microcrystals by intermolecular hydrogen bonding at a lower temperature, which induces PLA to form ample spherulites and "shish-kebab-like" structure rapidly. The effects of HBNA assembling behavior and nucleation activity on the PLA properties and the corresponding mechanism are systematically investigated. As a result, the crystallization temperature of PLA increased from 90 °C to 123 °C by adding as low as 0.75 wt% of HBNA, and the half-crystallization time (t1/2) at 135 °C decreased from 31.0 min to 1.5 min. More importantly, the PLA/HBNA maintains good transparency (transmittance > 75 % and haze is ca. 27 %) due to the decreased crystal size, even though the crystallinity of PLA is increased to 40 %, which also led to good heat resistance. The present work is expected to expand the application of PLA in packaging and other fields.

Battle tactics against MMP-9; discovery of novel non-hydroxamate MMP-9 inhibitors endowed with PI3K/AKT signaling attenuation and caspase 3/7 activation via Ugi bis-amide synthesis.

Matrix metalloproteinases (MMPs) are major modulators of the tumor microenvironment. They participate in extracellular matrix turnover, tumor growth, angiogenesis and metastasis. Accordingly, MMPs inhibition seems to be ideal solution to control cancer. Many MMPs inhibitors have been introduced ranging from hydroxamate-based peptidomimetics to the next generation non-hydroxamate inhibitors. Among MMPs, MMP-9 is attractive druggable anticancer target. Studies showed that inhibiting AKT, the central signaling node of MMP-9 upregulation, provides additional MMP-9 blockade. Furthermore, caspase-dependent AKT cleavage leads to cell death. Herein, Ugi MCR was utilized as a rapid combinatorial approach to generate various decorated bis-amide scaffolds as dual MMP-9/AKT inhibitors endowed with caspase 3/7 activation potential. The target adducts were designed to mimic the thematic structural features of non-hydroxamate MMP inhibitors. p-Nitrophenyl isonitrile 1 was utilized as structure entry to Ugi products with some structural similarities to amide-based caspase 3/7 activators. Besides, various acids, amines and aldehydes were employed as Ugi educts to enrich the SAR data. All adducts were screened for cytotoxicity against normal fibroblasts and three cancer cell lines; MCF-7, NFS-60 and HepG-2 utilizing MTT assay. 8, 11 and 28 were more active and safer than doxorubicin with single-digit nM IC50 and promising selectivity. Mechanistically, they exhibited dual MMP-9/AKT inhibition at single-digit nM IC50 with excellent selectivity over MMP-1,-2 and -13, and induced >51% caspase 3/7 activation. Consequently, they induced >49% apoptosis as detected by flow cytometric analysis, and inhibited cell migration (metastasis) up to 97% in cancer cells. Docking simulations were nearly consistent with enzymatic evaluation, also declared possible binding modes and essential structure features of active compounds. In silico physicochemical properties, ligand efficiency and drug-likeness metrics were reasonable for all adducts. Interestingly, 8 and 28 can be considered as drug-like candidates.

One-Dimensional Mercury Halide Coordination Polymers Based on A Semi-Rigid N-Donor Ligand: Reversible Structural Transformation.

Four one-dimensional (1D) mercury(II) halide coordination polymers have been synthesized by using a semi-rigid N-donor ligand, 2,2'-(1,4-phenylene)-bis(N-(pyridin-3-yl)acetamide) (1,4-pbpa). While [Hg(1,4-pbpa)Cl2·CH3OH]n, 1, forms a sinusoidal chain, the complexes [Hg(1,4-pbpa)X2]n (X = Cl, 2; Br, 3; I, 4) are helical. The sinusoidal 1 undergoes reversible structural transformation with helical 2 upon removal and uptake of CH3OH, which was accompanied with the conformation adjustment of the 1,4-pbpa ligand from trans anti-anti to trans syn-anti. Pyridyl ring rotation of the 1,4-pbpa ligand that results in the change of the ligand conformation is proposed for the initiation of the structural transformation.

Metal and Ligand Effects on the Construction of Divalent Coordination Polymers Based on bis-Pyridyl-bis-amide and Polycarboxylate Ligands.

Ten coordination polymers constructed from divalent metal salts, polycarboxylic acids, and bis-pyridyl-bis-amide ligands with different donor atom positions and flexibility are reported. They were structurally characterized by single-crystal X-ray diffraction. The ten coordination polymers are as follows: (1) {[Ni(L¹)(3,5-PDA)(H2O)3]·2H2O}n (L¹ = N,N'-di(3-pyridyl)suberoamide, 3,5-H2PDA = 3,5-pyridinedicarboxylic acid); (2) {[Ni2(L¹)2(1,3,5-HBTC)2(H2O)4]·H2O}n (1,3,5-H3BTC = 1,3,5-benzenetricarboxylic acid); (3) {[Ni(L²)(5-tert-IPA)(H2O)2]·2H2O}n (L² = N,N'-di(3-pyridyl)adipoamide, 5-tert-H2IPA = 5-tert-butylisophthalic acid); (4) [Ni(L³)1.5(5-tert-IPA)]n (L³ = N,N'-di(4-pyridyl)adipoamide); (5) [Co(L¹)(1,3,5-HBTC)(H2O)]n; (6) {[Co3(L¹)3(1,3,5-BTC)2(H2O)2]·6H2O}n; (7) [Cu(L4)(AIPA)]n (L4 = N,N'-bis(3-pyridinyl)terephthalamide, H2AIPA = 5-acetamido isophthalic acid); (8) {[Cu(L²)0.5(AIPA)]·MeOH}n; (9) {[Zn(L4)(AIPA)]·2H2O}n; and (10) {[Zn(L²)(AIPA)]·2H2O}n. Complex 1 forms a 1D chain and 2 is a two-fold interpenetrated 2D layer with the sql topology, while 3 is a 2D layer with the hcp topology and 4 shows a self-catenated 3D framework with the rare (4²·67·8)-hxg-d-5-C2/c topology. Different Co/1,3,5-H3BTC ratios were used to prepare 5 and 6, affording a 2D layer with the sql topology and a 2D layer with the (4·85)2(4)2(8³)2(8) topology that can be further simplified to an hcp topology. While complex 7 is a 2D layer with the (4²·67·8)(4²·6)-3,5L2 topology and 8 is a 2-fold interpenetrated 3D framework with the pcu topology, complexes 9 and 10 are self-catenated 3D frameworks with the (424·64)-8T2 and the (44·610·8)-mab topologies, respectively. The effects of the identity of the metal center, the ligand isomerism, and the flexibility of the spacer ligands on the structural diversity of these divalent coordination polymers are discussed. The luminescent properties of 9 and 10 and their photocatalytic effects on the degradation of dyes are also investigated.

Bis-amide transition metal complexes: isomerism and DNA interaction study.

A quatridentate bis-amide ligand, N,N'-propylenebis(salicylamide) H2pbs, and its transition metal complexes [M(pbs)(H2O)2], where M=Co(II), Ni(II), Cu(II), and Zn(II) have been synthesized and characterized by elemental analysis, UV-Vis, IR, NMR, Mass, EPR, molar conductivity, magnetic moment values and thermal analysis. The NMR spectrum of ligand evidences the E/Z isomerism. All the evidences reveal that the metal ions adopt octahedral geometry with metal:ligand:solvent ratio 1:1:2. The conductivity measurements exhibit that the complexes are non-electrolytes. DNA binding properties of these complexes have been explored by UV-Vis and cyclic voltammetry. The results indicate that these complexes are good intercalators.