Benzothiazole Aniline Research Articles

SYNTHESIS OF SOME BENZOTHIAZOLE ANILINE DERIVATIVES AND THEIR BIOLOGICAL ACTIVITIES

Three benzothiazole aniline derivatives 2a, 2b, and 2c were synthesized successfully by the reduction reaction of the respective nitro compound in neutral condition with Na2S2O4 in moderate yield. Structures of these derivatives were elucidated by IR, NMR, and MS analysis that referred to a strong agreement between spectral data and structures. Three compounds 2a, 2b, and 2c showed weak antioxidant, antibacterial and antifungal activities.

The Synthesis, Characterization, Molecular Docking and In Vitro Antitumor Activity of Benzothiazole Aniline (BTA) Conjugated Metal-Salen Complexes as Non-Platinum Chemotherapeutic Agents.

Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals to achieve selective and synergistic cytotoxicity. The compounds obtained were characterized by NMR spectroscopy, mass spectrometry, Fourier transform infrared spectroscopy, and elemental analysis. The compounds L, MnL, FeL, CoL, and ZnL showed promising in vitro cytotoxicity against cancer cells, and they had a lower IC50 than that of the clinically used cisplatin. In particular, MnL had synergistic cytotoxicity against liver, breast, and colon cancer cells. Moreover, MnL, CoL, and CuL promoted the production of reactive oxygen species in HepG2 tumor cell lines. The lead compound of this series, MnL, remained stable in physiological settings, and docking results showed that it interacted rationally with the minor groove of DNA. Therefore, MnL may serve as a viable alternative to platinum-based chemotherapy.

Synthesis, Characterization, and Anticancer Activity of Benzothiazole Aniline Derivatives and Their Platinum (II) Complexes as New Chemotherapy Agents.

We describe the synthesis, characterization, molecular modeling, and in vitro anticancer activity of three benzothiazole aniline (BTA) ligands and their corresponding platinum (II) complexes. We designed the compounds based on the selective antitumor properties of BTA, along with three types of metallic centers, aiming to take advantage of the distinctive and synergistic activity of the complexes to develop anticancer agents. The compounds were characterized using nuclear magnetic resonance spectrometry, Fourier transform infrared spectroscopy, mass spectrometry, elemental analysis, and tested for antiproliferative activity against multiple normal and cancerous cell lines. L1, L2, and L1Pt had better cytotoxicity in the liver, breast, lung, prostate, kidney, and brain cells than clinically used cisplatin. Especially, L1 and L1Pt demonstrated selective inhibitory activities against liver cancer cells. Therefore, these compounds can be a promising alternative to the present chemotherapy drugs.

Carbon nitride-based nanocaptor: An intelligent nanosystem with metal ions chelating effect for enhanced magnetic targeting phototherapy of Alzheimer's disease

Metal ions imbalance, a well-established pathologic feature of alzheimer's disease (AD), ultimately results in the deposition of amyloid-β peptide (Aβ) proteins and Aβ-induced neurotoxicity. Herein, to overcome these hurdles, an intelligent Aβ nanocaptor with the capacity to chelate metal ions and targeted therapy is developed by anchoring carbon nitride (C3N4) nanodots to Fe3O4@mesoporous silica nanospheres, and decorated with benzothiazole aniline (BTA) (designated as B–FeCN). The C3N4 nanodots could effectively capture superfluous Cu2+ to suppress the formation of Cu2+-Aβ complex thereby eliminating Aβ aggregation. Simultaneously, the nanocaptor enables local low-temperature hyperthermia to promote the dissolution of preformed fiber precipitates, therefore, maximizing the therapeutic benefits. Owing to its favorable photothermal effect, the blood-brain barrier (BBB) permeability of the nanocaptor is noticeably ameliorated upon laser illumination, which conquers the limitations associated with traditional anti-AD drugs, as evidenced by in vivo and in vitro studies. Besides, leveraging on the magnetic properties of Fe3O4 core, the nanocaptor is magnetized to access to the targeted Aβ regions under extrinsic magnetic field. BTA conjugation, which specifically binds to the β2 position of the Aβ fibers, executes specific targeting at Aβ plaques, and synchronously endows the BTA-modified nanocaptor with fluorescent imaging property for sensitively detecting Aβ aggregates. In view of these superiorities, nanocaptors combine metallostasis restoration and Aβ targeted therapy can surmount the interference of copper ions, enhance BBB permeability and protect cells against Aβ-induced neurotoxicity, which provides new avenues for developing neuroprotective nanosystems for the treatment of alzheimer's disease.

A Small Molecule Spinogenic Compound Enhances Functional Outcome and Dendritic Spine Plasticity in a Rat Model of Traumatic Brain Injury.

The tetra (ethylene glycol) derivative of benzothiazole aniline (SPG101) has been shown to improve dendritic spine density and cognitive memory in the triple transgenic mouse model of Alzheimer disease (AD) when administered intraperitoneally. The present study was designed to investigate the therapeutic effects of SPG101 on dendritic spine density and morphology and sensorimotor and cognitive functional recovery in a rat model of traumatic brain injury (TBI) induced by controlled cortical impact (CCI). Young adult male Wistar rats with CCI were randomly divided into the following two groups (n = 7/group): (1) Vehicle, and (2) SPG101. SPG101 (30 mg/kg) dissolved in vehicle (1% dimethyl sulfoxide in phosphate buffered saline) or Vehicle were intraperitoneally administered starting at 1 h post-injury and once daily for the next 34 days. Sensorimotor deficits were assessed using a modified neurological severity score and adhesive removal and foot fault tests. Cognitive function was measured by Morris water maze, novel object recognition (NOR), and three-chamber social recognition tests. The animals were sacrificed 35 days after injury, and their brains were processed for measurement of dendritic spine density and morphology using ballistic dye labeling. Compared with the vehicle treatment, SPG101 treatment initiated 1 h post-injury significantly improved sensorimotor functional recovery (days 7-35, p < 0.0001), spatial learning (days 32-35, p < 0.0001), NOR (days 14 and 35, p < 0.0001), social recognition (days 14 and 35, p < 0.0001). Further, treatment significantly increased dendritic spine density in the injured cortex (p < 0.05), decreased heterogeneous distribution of spine lengths in the injured cortex and hippocampus (p < 0.0001), modifications that are associated with the promotion of spine maturation in these brain regions. In summary, treatment with SPG101 initiated 1 h post-injury and continued for an additional 34 days improves both sensorimotor and cognitive functional recovery, indicating that SPG101 acts as a spinogenic agent and may have potential as a novel treatment of TBI.

Inhibition of glycogen synthase kinase-3 by BTA-EG4 reduces tau abnormalities in an organotypic brain slice culture model of Alzheimer\u2019s disease

Organotypic brain slice culture models provide an alternative to early stage in vivo studies as an integrated tissue system that can recapitulate key disease features, thereby providing an excellent platform for drug screening. We recently described a novel organotypic 3xTg-AD mouse brain slice culture model with key Alzheimer’s disease-like changes. We now highlight the potential of this model for testing disease-modifying agents and show that results obtained following in vivo treatment are replicated in brain slice cultures from 3xTg-AD mice. Moreover, we describe novel effects of the amyloid-binding tetra (ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, on tau. BTA-EG4 significantly reduced tau phosphorylation in the absence of any changes in the amounts of amyloid precursor protein, amyloid-β or synaptic proteins. The reduction in tau phosphorylation was associated with inactivation of the Alzheimer’s disease-relevant major tau kinase, GSK-3. These findings highlight the utility of 3xTg-AD brain slice cultures as a rapid and reliable in vitro method for drug screening prior to in vivo testing. Furthermore, we demonstrate novel tau-directed effects of BTA-EG4 that are likely related to the ability of this agent to inactivate GSK-3. Our findings support the further exploration of BTA-EG4 as a candidate therapeutic for Alzheimer’s disease.

Manganese Complex of Ethylenediaminetetraacetic Acid (EDTA)-Benzothiazole Aniline (BTA) Conjugate as a Potential Liver-Targeting MRI Contrast Agent.

A novel manganese(II) complex based on an ethylenediaminetetraacetic acid (EDTA) coordination cage bearing a benzothiazole aniline (BTA) moiety (Mn-EDTA-BTA) was designed and synthesized for use as a liver-specific MRI contrast agent with high chelation stability. In addition to forming a hydrophilic, stable complex with Mn2+, this new Mn chelate was rapidly taken up by liver hepatocytes and excreted by the kidneys and biliary system. The kinetic inertness and R1 relaxivity of the complex were much higher than those of mangafodipir trisodium (MnDPDP), a clinically approved liver-specific MRI contrast agent. The diagnostic utility of this new Mn complex in MRI was demonstrated by high-sensitivity tumor detection in an animal model of liver cancer.

Benzothiazole Amphiphiles Ameliorate Amyloid β-Related Cell Toxicity and Oxidative Stress.

Oxidative stress from the increase of reactive oxygen species in cells is a common part of the normal aging process and is accelerated in patients with Alzheimer's disease (AD). Herein, we report the evaluation of three benzothiazole amphiphiles (BAMs) that exhibit improved biocompatibility without loss of biological activity against amyloid-β induced cell damage compared to a previously reported hexa(ethylene glycol) derivative of benzothiazole aniline (BTA-EG6). The reduced toxicity of these BAM agents compared to BTA-EG6 corresponded with their reduced propensity to induce membrane lysis. In addition, all of the new BAMs were capable of protecting differentiated SH-SY5Y neuroblastoma cells from toxicity and concomitant oxidative stress induced by AD-related aggregated Aβ (1-42) peptides. Binding and microscopy studies support that these BAM agents target Aβ and inhibit the interactions of catalase with Aβ in cells, which, in turn, can account for an observed inhibition of Aβ-induced increases in hydrogen peroxide in cells treated with these compounds. These results support that this family of benzothiazole amphiphiles may have therapeutic potential for treating cellular damage associated with AD and other Aβ-related neurologic diseases.

Hexa (ethylene glycol) derivative of benzothiazole aniline promotes dendritic spine formation through the RasGRF1–Ras dependent pathway

Our recent study demonstrated that an amyloid-β binding molecule, BTA-EG4, increases dendritic spine number via Ras-mediated signaling. To potentially optimize the potency of the BTA compounds, we synthesized and evaluated an amyloid-β binding analog of BTA-EG4 with increased solubility in aqueous solution, BTA-EG6. We initially examined the effects of BTA-EG6 on dendritic spine formation and found that BTA-EG6-treated primary hippocampal neurons had significantly increased dendritic spine number compared to control treatment. In addition, BTA-EG6 significantly increased the surface level of AMPA receptors. Upon investigation into the molecular mechanism by which BTA-EG6 promotes dendritic spine formation, we found that BTA-EG6 may exert its effects on spinogenesis via RasGRF1-ERK signaling, with potential involvement of other spinogenesis-related proteins such as Cdc42 and CDK5. Taken together, our data suggest that BTA-EG6 boosts spine and synapse number, which may have a beneficial effect of enhancing neuronal and synaptic function in the normal healthy brain.

Correction: Megill et al., A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

Correction: Megill et al., A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

A tetra(ethylene glycol) derivative of benzothiazole aniline ameliorates dendritic spine density and cognitive function in a mouse model of Alzheimer's disease

We recently reported that the tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, acts as an amyloid-binding small molecule that promotes dendritic spine density and cognitive function in wild-type mice. This raised the possibility that BTA-EG4 may benefit the functional decline seen in Alzheimer's disease (AD). In the present study, we directly tested whether BTA-EG4 improves dendritic spine density and cognitive function in a well-established mouse model of AD carrying mutations in APP, PS1 and tau (APPswe;PS1M146V;tauP301L, 3xTg AD mice). We found that daily injections of BTA-EG4 for 2weeks improved dendritic spine density and cognitive function of 3xTg AD mice in an age-dependent manner. Specifically, BTA-EG4 promoted both dendritic spine density and morphology alterations in cortical layers II/III and in the hippocampus at 6–10months of age compared to vehicle-injected mice. However, at 13–16months of age, only cortical spine density was improved without changes in spine morphology. The changes in dendritic spine density correlated with Ras activity, such that 6–10month old BTA-EG4 injected 3xTg AD mice had increased Ras activity in the cortex and hippocampus, while 13–16month old mice only trended toward an increase in Ras activity in the cortex. Finally, BTA-EG4 injected 3xTg AD mice at 6–10months of age showed improved learning and memory; however, only minimal improvement was observed at 13–16months of age. This behavioral improvement corresponds to a decrease in soluble Aβ 40 levels. Taken together, these findings suggest that BTA-EG4 may be beneficial in ameliorating the synaptic loss seen in early AD.

Gadolinium Complex of DO3A-benzothiazole Aniline (BTA) Conjugate as a Theranostic Agent

A gadolinium complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and benzothiazole-aniline (BTA) of the type [Gd(DO3A-BTA)(H2O)] has been prepared for use as a single molecule theranostic agent. The kinetic inertness and r1 relaxivity (= 3.84 mM(-1) s(-1)) of the complex compare well with those of structurally analogous Gd-DOTA. The same complex is not only tumor-specific but also intracellular, enhancing MR images of cytosols and nuclei of tumor cells such as MCF-7, MDA-MB-231, and SK-HEP-1. Both DO3A-BTA and Gd(DO3A-BTA) reveal antiproliferative activities as demonstrated by GI50 and TGI values obtainable from the cell counting kit-8 (CCK-8) assays performed on these cell lines. Ex vivo and in vivo monitoring of tumor sizes provide parallel and supportive observations for such antiproliferative activities.

Benzothiazole Aniline Tetra(ethylene glycol) and 3-Amino-1,2,4-triazole Inhibit Neuroprotection against Amyloid Peptides by Catalase Overexpression in Vitro

Alzheimer's disease, Familial British dementia, Familial Danish dementia, Type 2 diabetes mellitus, plus Creutzfeldt-Jakob disease are associated with amyloid fibril deposition and oxidative stress. The antioxidant enzyme catalase is a neuroprotective amyloid binding protein. Herein the effects of catalase overexpression in SH-SY5Y neuronal cells on the toxicity of amyloid-β (Aβ), amyloid-Bri (ABri), amyloid-Dan (ADan), amylin (IAPP), and prion protein (PrP) peptides were determined. Results showed catalase overexpression was neuroprotective against Aβ, ABri, ADan, IAPP, and PrP peptides. The catalase inhibitor 3-amino-1,2,4-triazole (3-AT) and catalase-amyloid interaction inhibitor benzothiazole aniline tetra(ethylene glycol) (BTA-EG4) significantly enhanced neurotoxicity of amyloid peptides in catalase overexpressing neuronal cells. This suggests catalase neuroprotection involves breakdown of hydrogen peroxide (H2O2) plus a direct binding interaction between catalase and the Aβ, ABri, ADan, IAPP, and PrP peptides. Kisspeptin 45-50 had additive neuroprotective actions against the Aβ peptide in catalase overexpressing cells. The effects of 3-AT had an intracellular site of action, while catalase-amyloid interactions had an extracellular component. These results suggest that the 3-AT and BTA-EG4 compounds may be able to inhibit endogenous catalase mediated neuroprotection. Use of BTA-EG4, or compounds that inhibit catalase binding to amyloid peptides, as potential therapeutics for Neurodegenerative diseases may therefore result in unwanted effects.

A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from Aβ-induced toxicity. However, the effects of Aβ-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aβ levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG4-mediated behavioral improvement is not correlated with LTP, but with increased spinogenesis. The higher dendritic spine density reflects an increase in the number of functional synapses as determined by increased miniature EPSC (mEPSC) frequency without changes in presynaptic parameters or postsynaptic mEPSC amplitude. Additionally, BTA-EG4 requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG4 may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy.

Oligovalent amyloid-binding agents reduce SEVI-mediated enhancement of HIV-1 infection.

This paper evaluates the use of oligovalent amyloid-binding molecules as potential agents that can reduce the enhancement of human immunodeficiency virus-1 (HIV-1) infection in cells by semen-derived enhancer of virus infection (SEVI) fibrils. These naturally occurring amyloid fibrils found in semen have been implicated as mediators that can facilitate the attachment and internalization of HIV-1 virions to immune cells. Molecules that are capable of reducing the role of SEVI in HIV-1 infection may, therefore, represent a novel strategy to reduce the rate of sexual transmission of HIV-1 in humans. Here, we evaluated a set of synthetic, oligovalent derivatives of benzothiazole aniline (BTA, a known amyloid-binding molecule) for their capability to bind cooperatively to aggregated amyloid peptides and to neutralize the effects of SEVI in HIV-1 infection. We demonstrate that these BTA derivatives exhibit a general trend of increased binding to aggregated amyloids as a function of increasing valence number of the oligomer. Importantly, we find that oligomers of BTA show improved capability to reduce SEVI-mediated infection of HIV-1 in cells compared to a BTA monomer, with the pentamer exhibiting a 65-fold improvement in efficacy compared to a previously reported monomeric BTA derivative. These results, thus, support the use of amyloid-targeting molecules as potential supplements for microbicides to curb the spread of HIV-1 through sexual contact.

Self-assembled, cation-selective ion channels from an oligo(ethylene glycol) derivative of benzothiazole aniline

This paper describes the spontaneous formation of well-defined pores in planar lipid bilayers from the self-assembly of a small synthetic molecule that contains a benzothiazole aniline (BTA) group attached to a tetra-ethylene glycol (EG4) moiety. Macroscopic and single-channel current recordings suggest that these pores are formed by the assembly of four BTA-EG4 monomers with an open pore diameter that appears similar to the one of gramicidin pores (~0.4nm). The single-channel conductance of these pores is modulated by the pH of the electrolyte and has a minimum at pH ~3. Self-assembled pores from BTA-EG4 are selective for monovalent cations and have long open channel lifetimes on the order of seconds. BTA-EG4 monomers in these pores appear to be arranged symmetrically across both leaflets of the bilayer, and spectroscopy studies suggest that the fluorescent BTA group is localized inside the lipid bilayers. In terms of biological activity, BTA-EG4 molecules inhibited growth of gram-positive Bacillus subtilis bacteria (IC50 ~50μM) and human neuroblastoma SH-SY5Y cells (IC50 ~60μM), while they were not toxic to gram-negative Escherichia coli bacteria at a concentration up to 500μM. Based on these properties, this drug-like, synthetic, pore-forming molecule with a molecular weight below 500gmol−1 might be appealing as a starting material for development of antibiotics or membrane-permeating moieties for drug delivery. From a biophysical point of view, long-lived, well-defined ion-selective pores from BTA-EG4 molecules offer an example of a self-assembled synthetic supramolecule with biological function.

Amyloid-binding Small Molecules Efficiently Block SEVI (Semen-derived Enhancer of Virus Infection)- and Semen-mediated Enhancement of HIV-1 Infection

Semen was recently shown to contain amyloid fibrils formed from a self-assembling peptide fragment of the protein prostatic acid phosphatase. These amyloid fibrils, termed semen-derived enhancer of virus infection, or SEVI, have been shown to strongly enhance HIV infectivity and may play an important role in sexual transmission of HIV, making them a potential microbicide target. One novel approach to target these fibrils is the use of small molecules known to intercalate into the structure of amyloid fibrils, such as derivatives of thioflavin-T. Here, we show that the amyloid-binding small molecule BTA-EG6 (the hexa(ethylene glycol) derivative of benzothiazole aniline) is able to bind SEVI fibrils and effectively inhibit both SEVI-mediated and semen-mediated enhancement of HIV infection. BTA-EG6 also blocks the interactions of SEVI with HIV-1 virions and HIV-1 target cells but does not cause any inflammation or toxicity to cervical epithelial cells. These results suggest that an amyloid-binding small molecule may have utility as a microbicide, or microbicidal supplement, for HIV-1.

Synthesis and biological evaluation of 99mTc, Re-monoamine-monoamide conjugated to 2-(4-aminophenyl)benzothiazole as potential probes for β-amyloid plaques in the brain

The benzothiazole aniline (BTA) conjugated with monoamine-monoamide (MAMA) was synthesized and then labeled with (99m)Tc. Its corresponding rhenium analogue was synthesized, and the fluorescent staining was performed in brain sections of both Tg mouse and Alzheimer's disease (AD) patient. The fluorescent rhenium complex Re-MAMA-BTA selectively bound to the amyloid aggregates in the brain sections of both APP Tg mouse and AD patient. The analogous (99m)Tc-MAMA-BTA complex could enter the normal mouse brain with high initial uptake. These results are encouraging for further exploration of their derivatives as imaging agents for Abeta plaques in the brain.