Discovery of 6-Acylamino/Sulfonamido Benzoxazolone with IL-6 Inhibitory Activity as Promising Therapeutic Agents for Ulcerative Colitis.

Ulcerative colitis has been widely concerned for its persistent upward trend, and the sustained overproduction of pro-inflammatory cytokines such as IL-6 remains a crucial factor in the development of UC. Therefore, the identification of new effective drugs to block inflammatory responses is an urgent and viable therapeutic strategy for UC. In our research, twenty-three 6-acylamino/sulfonamido benzoxazolone derivatives were synthesized, characterized, and evaluated for anti-inflammatory activity against NO and IL-6 production in LPS-induced RAW264.7 cells. The results demonstrated that most of the target compounds were capable of reducing the overexpression of NO and IL-6 to a certain degree. For the most active compounds 3i, 3j and 3 l, the inhibitory activities were superior or equivalent to those of the positive drug celecoxib with a dose-dependent relationship. Furthermore, animal experiments revealed that active derivatives 3i, 3j and 3 l exhibited definitive therapeutical effect on DSS induced ulcerative colitis in mice by mitigating weight loss and DAI score while decreasing levels of pro-inflammatory cytokines such as IL-6 and IFN-γ, simultaneously increasing production of anti-inflammatory cytokines IL-10. In addition, compounds 3i, 3j and 3 l could also inhibit the oxidative stress to alleviate ulcerative colitis by decreasing MDA and MPO levels. These finding demonstrated that compounds 3i, 3j and 3 l hold significant potential as novel therapeutic agents for ulcerative colitis.

Benzimidazole and Benzoxazole Derivatives Against Alzheimer's Disease.

Benzimidazole and benzoxazole derivatives are included in the category of medical drugs in a wide range of areas such as anticancer, anticoagulant, antihypertensive, anti- inflammatory, antimicrobial, antiparasitic, antiviral, antioxidant, immunomodulators, proton pump inhibitors, hormone modulators, etc. Many researchers have focused on synthesizing more effective benzimidazole and benzoxazole derivatives for screening various biological activities. In addition, there are benzimidazole and benzoxazole rings as bioisosteres of aromatic rings found in drugs used in the treatment of Alzheimer's disease. Because of the diverse activity of the benzimidazole and benzoxazole rings and bioisosteres marketed as drugs for Alzheimer Diseases, designed compounds containing these rings are likely to be effective against Alzheimer's disease. In this study, the effectiveness of compounds containing benzimidazole and benzoxazole rings against Alzheimer's disease will be examined.

S-Dihydrodaidzein and 3-(1,3-benzoxazol-2-yl)-benzamide, Two New Potential ß-estrogen Receptor Ligands with Anti-adipogenic Activity.

BACKGROUND: The elucidation of molecular pathways associated with adipogenesis has evidenced the relevance of estrogen and estrogen receptor beta (ERß). The positive effects of ERß ligands on adipogenesis, energy expenditure, lipolysis, food intake, and weight loss, make ERß an attractive target for obesity control. From ligand-based virtual screening, molecular docking, and molecular dynamic simulations, six new likely ERß ligands (C1 to C6) have been reported with potential for pharmacological obesity treatment. OBJECTIVE: In this study, the effect of molecules C1-C6 on adipogenesis using the murine 3T3-L1 cell line was evaluated. METHODS: Cell viability was assessed by MTT assays. Lipid accumulation and gene expression were investigated by ORO staining and real-time quantitative RT-PCR experiments, respectively. RESULTS: Cell viability was not significantly affected by C1-C6 at concentrations up to 10 µM. Interestingly, treatment with 10 µM of C1 (S-Dihydrodaidzein) and C2 (3-(1,3-benzoxazol-2-yl)- benzamide) for 72 h inhibited adipocyte differentiation; moreover, ORO staining evidenced a reduced intracellular lipid accumulation (40% at day 7). Consistently, mRNA expression of the adipogenic markers, PPARγ and C/EBPα, was reduced by 50% and 82%, respectively, in the case of C1, and by 83% and 59%, in the case of C2. CONCLUSION: Altogether, these results show the two new potential ß-estrogen receptor ligands, C1 and C2, to exhibit anti-adipogenic activity. They could further be used as lead structures for the development of more efficient drugs for obesity control.

New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies.

A new series of benzoxazole derivatives were designed and synthesised to have the main essential pharmacophoric features of VEGFR-2 inhibitors. Cytotoxic activities were evaluated for all derivatives against two human cancer cell lines, MCF-7 and HepG2. Also, the effect of the most cytotoxic derivatives on VEGFR-2 protein concentration was assessed by ELISA. Compounds 14o, 14l, and 14b showed the highest activities with VEGFR-2 protein concentrations of 586.3, 636.2, and 705.7 pg/ml, respectively. Additionally, the anti-angiogenic property of compound 14b against human umbilical vascular endothelial cell (HUVEC) was performed using a wound healing migration assay. Compound 14b reduced proliferation and migratory potential of HUVEC cells. Furthermore, compound 14b was subjected to further biological investigations including cell cycle and apoptosis analyses. Compound 14b arrested the HepG2 cell growth at the Pre-G1 phase and induced apoptosis by 16.52%, compared to 0.67% in the control (HepG2) cells. The effect of apoptosis was buttressed by a 4.8-fold increase in caspase-3 level compared to the control cells. Besides, different in silico docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR-2 active sites.

2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases.

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (Ki within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (Ki > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.

Design, synthesis and biological evaluation of novel hybrids targeting mTOR and HDACs for potential treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major contributor to global cancer incidence and mortality. Many pathways are involved in the development of HCC and various proteins including mTOR and HDACs have been identified as potential drug targets for HCC treatment. In the present study, two series of novel hybrid molecules targeting mTOR and HDACs were designed and synthesized based on parent inhibitors (MLN0128 and PP121 for mTOR, SAHA for HDACs) by using a fusion-type molecular hybridization strategy. In vitro antiproliferative assays demonstrated that these novel hybrids with suitable linker lengths exhibited broad cytotoxicity against various cancer cell lines, with significant activity against HepG2 cells. Notably, DI06, an MLN0128-based hybrid, exhibited antiproliferative activity against HepG2 cells with an IC50 value of 1.61 µM, which was comparable to those of both parent drugs (MLN0128, IC50 = 2.13 µM and SAHA, IC50 = 2.26 µM). In vitro enzyme inhibition assays indicated that DI06, DI07 and DI17 (PP121-based hybrid) exhibited nanomolar inhibitory activity against mTOR kinase and HDACs (e.g., HDAC1, HDAC2, HDAC3, HADC6 and HADC8). Cellular studies and western blot analyses uncovered that in HepG2 cells, DI06 and DI17 induced cell apoptosis by targeting mTOR and HDACs, blocked the cell cycle at the G0/G1 phase and suppressed cell migration. The potential binding modes of the hybrids (DI06 and DI17) with mTOR and HDACs were investigated by molecular docking. DI06 displayed better stability in rat liver microsomes than DI07 and DI17. Collectively, DI06 as a novel mTOR and HDACs inhibitor presented here warrants further investigation as a potential treatment of HCC.

A Patent Review on the Current Developments of Benzoxazoles in Drug Discovery.

The benzoxazole moiety is widely found in various natural compounds, which are often found to be biologically active. Due to its versatile biological properties, benzoxazole has been incorporated as an essential pharmacophore and substructure in many medicinal compounds. In the past years, numerous benzoxazole derivatives have been synthesised and evaluated for their biological potential. The wide range in therapeutic potential of benzoxazole derivatives is related to the favourable interactions of the benzoxazole moiety with different protein targets. Herein we review the biological activities of benzoxazole derivatives patented within the past six years. Using the Lens database, granted patents issued from 2015 to 2020 were retrieved. The patented benzoxazole derivatives demonstrated excellent activity against various protein targets and diseases, with some reaching clinical trial stage. Pharmacological and medicinal aspects of patented benzoxazole derivatives are discussed. The recent development and drawbacks are also reviewed.

Exploiting the HSP60/10 chaperonin system as a chemotherapeutic target for colorectal cancer.

Over the past few decades, an increasing variety of molecular chaperones have been investigated for their role in tumorigenesis and as potential chemotherapeutic targets; however, the 60 kDa Heat Shock Protein (HSP60), along with its HSP10 co-chaperone, have received little attention in this regard. In the present study, we investigated two series of our previously developed inhibitors of the bacterial homolog of HSP60/10, called GroEL/ES, for their selective cytotoxicity to cancerous over non-cancerous colorectal cells. We further developed a third "hybrid" series of analogs to identify new candidates with superior properties than the two parent scaffolds. Using a series of well-established HSP60/10 biochemical screens and cell-viability assays, we identified 24 inhibitors (14%) that exhibited > 3-fold selectivity for targeting colorectal cancer over non-cancerous cells. Notably, cell viability EC50 results correlated with the relative expression of HSP60 in the mitochondria, suggesting a potential for this HSP60-targeting chemotherapeutic strategy as emerging evidence indicates that HSP60 is up-regulated in colorectal cancer tumors. Further examination of five lead candidates indicated their ability to inhibit the clonogenicity and migration of colorectal cancer cells. These promising results are the most thorough analysis and first reported instance of HSP60/10 inhibitors being able to selectively target colorectal cancer cells and highlight the potential of the HSP60/10 chaperonin system as a viable chemotherapeutic target.

Discovery of 5-(or 6)-benzoxazoles and oxazolo[4,5-b]pyridines as novel candidate antitumor agents targeting hTopo IIα.

Discovery of novel anticancer drugs which have low toxicity and high activity is very significant area in anticancer drug research and development. One of the important targets for cancer treatment research is topoisomerase enzymes. In order to make a contribution to this field, we have designed and synthesized some 5(or 6)-nitro-2-(substitutedphenyl)benzoxazole (1a-1r) and 2-(substitutedphenyl)oxazolo[4,5-b]pyridine (2a-2i) derivatives as novel candidate antitumor agents targeting human DNA topoisomerase enzymes (hTopo I and hTopo IIα). Biological activity results were found very promising for the future due to two compounds, 5-nitro-2-(4-butylphenyl)benzoxazole (1i) and 2-(4-butylphenyl)oxazolo[4,5-b]pyridine (2i), that inhibited hTopo IIα with 2 µM IC50 value. These two compounds were also found to be more active than reference drug etoposide. However, 1i and 2i did not show any satisfactory cyctotoxic activity on the HeLa, WiDR, A549, and MCF7 cancer cell lines. Moreover, molecular docking and molecular dynamic simulations studies for the most active compounds were applied in order to understand the mechanism of inhibition activity of hTopo IIα. In addition, in silico ADME/Tox studies were performed to predict drug-likeness and pharmacokinetic properties of all the tested compounds.

Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story.

Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.

Amidino substituted 2-aminophenols: biologically important building blocks for the amidino-functionalization of 2-substituted benzoxazoles.

Unlike the closely related and widely investigated amidino-substituted benzimidazoles and benzothiazoles with a range of demonstrated biological activities, the matching benzoxazole analogues still remain a largely understudied and not systematically evaluated class of compounds. To address this challenge, we utilized the Pinner reaction to convert isomeric cyano-substituted 2-aminophenols into their amidine derivatives, which were isolated as hydrochlorides and/or zwitterions, and whose structure was confirmed by single crystal X-ray diffraction. The key step during the Pinner synthesis of the crucial carboximidate intermediates was characterized through mechanistic DFT calculations, with the obtained kinetic and thermodynamic parameters indicating full agreement with the experimental observations. The obtained amidines were subjected to a condensation reaction with aryl carboxylic acids that allowed the synthesis of a new library of 5- and 6-amidino substituted 2-arylbenzoxazoles. Their antiproliferative features against four human tumour cell lines (SW620, HepG2, CFPAC-1, HeLa) revealed sub-micromolar activities on SW620 for several cyclic amidino 2-naphthyl benzoxazoles, thus demonstrating the usefulness of the proposed synthetic strategy and promoting amidino substituted 2-aminophenols as important building blocks towards biologically active systems.

Antiproliferative activity, enzymatic inhibition and apoptosis-promoting effects of benzoxazole-based hybrids on human breast cancer cells.

New benzoxazole derivatives containing 1,3,4-oxadiazole, 1,2,4-triazole or triazolothiadiazine rings were synthesized and screened for their in vitro antiproliferative activities against MCF-7 and MDA-MB-231 breast cancer cell lines using MTT assay. Doxorubicin, cisplatin and 2-(4-aminophenyl)benzothiazole (CJM 126) were used as references. The most active compounds 7a, 8d, 8e and 10c were screened for their antiproliferative activities against MCF-10A normal breast cells where compounds 8e and 7a were the most selective towards MCF-7 and MDA-MB-231 cell lines, respectively compared to CJM 126. In vitro enzymatic inhibition assays of epidermal growth factor receptor (EGFR) and aromatase (ARO) enzymes were performed. Compound 7a showed inhibition of EGFR comparable to that of erlotinib while compound 8e exhibited nearly half the inhibitory activity of erlotinib towards EGFR and was more potent inhibitor of ARO than letrozole. Caspase-9 activation assay, cell cycle analysis and Annexin-V/ Propidium iodide assay performed for compounds 7a, 8d, 8e and 10c demonstrated over expression of caspase-9 protein level, pre G1 apoptosis and high annexin V binding affinity. Therefore, these compounds are considered as potent apoptosis-promoting agents. The predicted docking studies and in silico chemo-informatic properties of compounds 7a and 8e were appropriate. Compounds 7a and 8e are promising anti-breast cancer agents exhibiting potent apoptosis-promoting properties.

Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53.

We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure-activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo.

A new series of benzoxazole-based SIRT1 modulators for targeted therapy of non-small-cell lung cancer.

In an attempt to identify potential anticancer agents for non-small-cell lung cancer (NSCLC) targeting sirtuin 1 (SIRT1), the synthesis of a new series of benzoxazoles (3a - i) was carried out through a facile and versatile synthetic route. The compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cells using the MTT assay. 2-[(5-Nitro-1H-benzimidazol-2-yl)thio]-N-(2-methylbenzoxazol-5-yl)acetamide (3e) and 2-[(5-chloro-1H-benzimidazol-2-yl)thio]-N-(2-methylbenzoxazol-5-yl)acetamide (3g) were the most potent and selective anticancer agents in this series against the A549 cell line, with IC50 values of 46.66 ± 11.54 and 55.00 ± 5.00 µM, respectively. The flow cytometry-based apoptosis detection assay was performed to determine their effects on apoptosis in A549 cells. Both compounds induced apoptosis in a dose-dependent manner. The effects of compounds 3e and 3g on SIRT1 activity were determined. On the basis of in vitro studies, it was observed that compound 3g caused a significant decrease in SIRT1 levels in a dose-dependent manner, whereas compound 3e increased the SIRT1 levels. According to molecular docking studies, the substantial alteration in the type of action could be attributed to the difference between the interactions of compounds 3e and 3g with the same residues in the active site of SIRT1 (PDB code: 4IG9). On the basis of in silico ADME (absorption, distribution, metabolism, and excretion) studies, these compounds are predicted to possess favorable ADME profiles. According to the in vitro and in silico studies, compounds 3e and 3g, small-molecule SIRT1 modulators, were identified as potential orally bioavailable anticancer agents for the targeted therapy of NSCLC.

Synthesis and Apoptotic Activities of New 2(3H)-benzoxazolone Derivatives in Breast Cancer Cells.

BACKGROUND: 2(3H)-Benzoxazolone derivatives are preferential structural blocks in pharmacological probe designing with the possibility of modifications at various positions on the core structure. Benzoxazolones showed various biological activities such as analgesics, anti-inflammatory and anti-cancer. OBJECTIVE: In the present work, we have prepared new Mannich bases of 2(3H)-benzoxazolone derivatives and evaluated their cytotoxicities and proapoptotic properties in MCF-7 breast cancer cell line. METHODS: The structures of these compounds were characterized by FT-IR, elemental analysis, 1H and 13C NMR. Cytotoxicities of all the target compounds were investigated by MTT assay. Apoptotic properties of compounds were evaluated by immunocytochemistry using antibodies against caspase-3, cytochrome-c, FasL, and also TUNEL assay. RESULTS: These two novel compounds, 1 and 2, both have the same piperazine substituent on the nitrogen atom of benzoxazolone and the main difference in the structures of these compounds is the presence of Cl substituent at the 5- position of the benzoxazolone ring. MTT results showed that compounds 1 and 2 were effective in terms of reduction of cell viability at 100µM and 50µM concentration for 48h, respectively. As a result of immunohistochemical staining, Fas L and caspase-3 immunoreactivities were significantly increased in MCF-7 cells after treatment with compound 1. Additionally, caspase-3 and cytochrome-c immunoreactivities were also increased significantly in MCF-7 cells after treatment with compound 2. The number of TUNEL positive cells was significantly higher in MCF-7 cells when compared with the control group after treatment with both compounds 1 and 2. CONCLUSION: It could be concluded that N-substituted benzoxazolone derivatives increase potential anti-cancer effects and they could be promising novel therapeutic agents for chemotherapy.

Synthesis of some new benzoxazole derivatives and investigation of their anticancer activities.

Phortress is an anticancer prodrug, which has active metabolite (5F-203) being potent agonist of the aryl hydrocarbon receptor (AhR). The 5F-203 switches on cytochrome P450 CYP1A1 gene expression and thus exhibits anticancer activity. In this study, it is aimed to obtain new phortress analogues by bioisosteric replacement of benzothiazole core in the structure to benzoxazole ring system. Synthesis of compounds (3a-3p) were performed according to literature methods. Their structures were elucidated by IR, 1H NMR, 13C NMR, 2D-NMR and HRMS spectroscopic methods. Cytotoxicity (MTT), inhibition of DNA synthesis and flow cytometric analysis assays were applied to determine anticancer activity of the compounds on colon (HT-29), breast (MCF7), lung (A549), liver (HepG2) and brain (C6) carcinoma cell types. When compared reference agent doxorubicin, compounds 3m and 3n displayed very attractive anticancer effect against carcinogenic cell lines. Due to structural similarity to phortress, biotransformation studies for 3m and 3n were examined by LCMS-IT-TOF system and probable metabolites of these compounds were determined. Induction potential of these compounds on CYP1A1/2 enzymes was also investigated to clarify possible mechanism of action. Interaction modes between CYP1A1 enzyme and compound 3n or its some metabolites were investigated by docking studies. In conclusion, findings of these study indicate that compounds 3m and 3n possess significant anticancer activity, probably with the same mechanism of action to Phortress.

Docking Studies and Antiproliferative Activities of 6-(3-aryl-2-propenoyl)-2(3H)- benzoxazolone Derivatives as Novel Inhibitors of Phosphatidylinositol 3-Kinase (PI3Kα).

BACKGROUND: Cancer is a life-threatening group of diseases and universally, the second main cause of death. The design and development of new scaffolds targeting selective cancer cells are considered a promising goal for cancer treatment. AIMS AND OBJECTIVE: Chalcone derivatives; 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolone, were previously prepared and evaluated against the oral cavity squamous cell carcinoma cell line, HSC-2, and were reported to have remarkably high tumor selectivity. The aim of this study was to further investigate the anticancer activities of the chalcone derivatives against human colon cancer cells with a possible elucidation of their mechanism of action. METHODS: Computational studies were conducted to explore the potential interaction of the synthesized molecules with the phosphatidylinositol-4,5-bisphosphate 3-kinaseα (PI3Kα). Biological evaluation of the antiproliferative activities associated with compounds 1-23 was carried out against the colon cancer cell line, HCT116. Lactate Dehydrogenase (LDH) activity was measured to study necrosis, while the caspase-3 activation and DNA measurements were used to evaluate apoptosis in the treated cells. RESULTS: Glide studies against PI3Kα kinase domain demonstrated that the 6-(3-aryl-2-propenoyl)-2(3H)- benzoxazolone scaffold forms H-bond with K802, Y836, E849, V851, N853, Q859, and D933, and it fits the fingerprint of PI3Kα active inhibitors. Biological evaluation of the reported compounds in HCT116 cell line confirmed that the series inhibited PI3Kα activity and induced apoptosis via activation of caspase-3 and reduction of DNA content. CONCLUSION: The recently developed compounds might be employed as lead structures for the design of new antitumor drugs targeting PI3Kα.

Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on ß-Amyloid-Induced PC12 Cells.

A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a-5v) exerted neuroprotective effects on ß-amyloid (Aß)-induced PC12 cells as a potential approach for the treatment of Alzheimer's disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aß25-35-induced PC12 cells at 5 µg/mL. We found that compound 5c was non-neurotoxic at 30 µg/mL and significantly increased the viability of Aß25-35-induced PC12 cells at 1.25, 2.5 and 5 µg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3ß) and decreased the expression of nuclear factor-κB (NF-κB) in Aß25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aß25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), ß-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3ß/NF-κB signaling pathway. In vivo studies suggest that compound 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.

Design of Novel 4-Aminobenzofuroxans and Evaluation of Their Antimicrobial and Anticancer Activity.

A series of novel 4-aminobenzofuroxan derivatives containing aromatic/aliphatic amines fragments was achieved via aromatic nucleophilic substitution reaction of 4,6-dichloro-5-nitrobenzofuroxan. The quantum chemistry calculations were performed to identify the factors affecting the regioselectivity of the reaction. The formation of 4-substituted isomer is favored both by its greater stability and the lower activation barrier. Antimicrobial activity of the obtained compounds has been evaluated and some of them were found to suppress effectively bacterial biofilm growth. Fungistatic activity of 4-aminobenzofuroxans were tested on two genetically distinct isolates of M. nivale. The effect of some benzofuroxan derivatives is likely to be more universal against different varieties of M. nivale compared with benzimidazole and carbendazim. Additionally, their anti-cancer activity in vitro has been tested. 4-aminofuroxans possessing aniline moiety showed a high selectivity towards MCF-7 and M-HeLa tumor cell lines. Moreover, they exhibit a significantly lower toxicity towards normal liver cells compared to Doxorubicin and Tamoxifen. Thus, benzofuroxans containing aromatic amines fragments in their structure are promising candidates for further development both as anti-cancer and anti-microbial agents.

New halogenated chalcones with cytotoxic and carbonic anhydrase inhibitory properties: 6-(3-Halogenated phenyl-2-propen-1-oyl)-2(3H)-benzoxazolones.

In this study, novel halogenated chalcones, 6-(3-halogenated phenyl-2-propen-1-one)-2(3H)-benzoxazolones (2a-n), were synthesized for the first time (except 2a), and their chemical structures were characterized by 1 H nuclear magnetic resonance (NMR), 13 C NMR, and high-resolution mass spectrometry spectra. Cytotoxic activities and carbonic anhydrase (CA) inhibitory effects of the compounds were studied to identify new possible drug candidate molecules. Cytotoxicity results pointed out that compound 2m, 6-[3-(3-bromophenyl)-2-propenoyl]-2(3H)-benzoxazolone, had the highest cytotoxicity (CC50 ) and potency selectivity expression (PSE) values. Thus, compound 2m can be considered as a lead compound of the series in terms of cytotoxicity. When the CA inhibition results of the compounds were evaluated, it was found that the Ki values of the compounds ranged from 30.5 ± 11.3 to 65.5 ± 25.6 µM toward hCA I, and they ranged from 7.3 ± 1.8 to 58.8 ± 12.3 µM toward hCA II. However, the Ki values of the reference drug, acetazolamide (AZA), were 30.2 ± 7.8 and 4.4 ± 0.6 µM toward hCA I and hCA II, respectively. According to the results obtained, compounds 2a-n had lower Ki values than AZA, whereas compounds 2a, 2b, 2e-g, 2l, and 2n had similar Ki values, compared with AZA. So, the compounds 2a, 2b, 2e-g, 2l, and 2n can be considered as lead molecules of this series for further considerations.