Exploring chalcone-sulfonyl piperazine hybrids as anti-diabetes candidates: design, synthesis, biological evaluation, and molecular docking study.

To address the escalating rates of diabetes mellitus worldwide, there is a growing need for novel compounds. The demand for more affordable and efficient methods of managing diabetes is increasing due to the inevitable side effects associated with existing antidiabetic medications. In this present research, various chalcone-sulfonyl piperazine hybrid compounds (5a-k) were designed and synthesized to develop inhibitors against alpha-glucosidase and alpha-amylase. In addition, several spectroscopic methods, including FT-IR, 1H-NMR, 13C-NMR, and HRMS, were employed to confirm the exact structures of the synthesized derivatives. All synthesized compounds were evaluated for their ability to inhibit alpha-glucosidase and alpha-amylase in vitro using acarbose as the reference standard and they showed excellent to good inhibitory potentials. Compound 5k exhibited excellent inhibitory activity against alpha-glucosidase (IC50 = 0.31 ± 0.01 µM) and alpha-amylase (IC50 = 4.51 ± 1.15 µM), which is 27-fold more active against alpha-glucosidase and 7-fold more active against alpha-amylase compared to acarbose, which had IC50 values of 8.62 ± 1.66 µM for alpha-glucosidase and 30.97 ± 2.91 µM for alpha-amylase. It was discovered from the Lineweaver-Burk plot that 5k exhibited competitive inhibition against alpha-glucosidase. Furthermore, cytotoxicity screening assay results against human fibroblast HT1080 cells showed that all compounds had a good level of safety profile. To explore the binding interactions of the most potent compound (5k) with the active site of enzymes, molecular docking research was conducted, and the results obtained supported the experimental data.

Synthesis, anticancer evaluation, and molecular docking studies of thiazolyl-pyrazoline derivatives.

The molecular hybridization of thiazole and pyrazoline heterocyclic structures with diverse activities appears to be an interesting strategy for developing new anticancer compounds. This study presents the synthesis of eleven new thiazolyl-pyrazoline derivatives (7a-k) and the evaluation of their in-vitro anti-proliferative activities against human lung carcinoma (A549) and human melanoma cancer (A375) cell lines through MTT assay. In comparison to the positive reference drug erlotinib (IC50 = 34.16 µM in A549 and IC50 = 25.85 µM in A375), four compounds (7e, 7h, 7j, and 7k) were identified as the most active against both cell lines (especially compound 7k with IC50 = 20.28 µM in A549 and 16.08 µM in A375). Additionally, these potent compounds were selected to be investigated for their anti-metastasis and anti-inflammatory properties via inhibition of the expression of matrix metalloproteinase 2, 9 (MMP-2, 9) and cyclooxygenase 2 (COX-2). In A549 cells, upon exposure to compounds 7e and 7j, COX-2 expression is decreased, whereas compounds 7e, 7j, and 7k reduced COX-2 expression in A375 cell lines. Molecular docking studies were carried out to show the possible interactions of synthesized compounds with the predicted active site of the COX-2 protein. The results revealed that compounds 7e and 7j can bind well to the active site of COX-2 protein. Collectively, compounds 7e, 7j, and 7k are all promising candidates for further research towards the development of novel anticancer agents.

Design and synthesis of thiadiazole-oxadiazole-acetamide derivatives: Elastase inhibition, cytotoxicity, kinetic mechanism, and computational studies.

Considering the biological significance of 1,3,4-thiadiazole/oxadiazole heterocyclic scaffolds, a novel series of 1,3,4-thiadiazole-1,3,4-oxadiazole-acetamide derivatives (7a-j) was designed and synthesized using molecular hybridization. The inhibitory effects of the target compounds on elastase were evaluated, and all of these molecules were found to be potent inhibitors compared to the standard reference oleanolic acid. Compound 7f exhibited the excellent inhibitory activity (IC50 = 0.06 ± 0.02 µM), which is 214-fold more active than oleanolic acid (IC50 = 12.84 ± 0.45 µM). Kinetic analysis was also performed on the most potent compound (7f) to determine the mode of binding with the target enzyme, and it was discovered that 7f inhibits the enzyme in a competitive manner. Furthermore, the MTT assay method was used to assess their toxicity on the viability of B16F10 melanoma cell lines, and all compounds did not display any toxic effect on the cells even at high concentrations. The molecular docking studies of all compounds also justified with their good docking score and among them, compound 7f had a good conformational state with hydrogen bond interactions within the receptor binding pocket, which is consistent with the experimental inhibition studies.

Synthesis, carbonic anhydrase inhibition, anticancer activity, and molecular docking studies of 1,3,4-oxadiazole derivatives.

In this work, we have synthesized various organic compounds possessing 1,3,4-oxadiazole as a core structure and the structure of the newly synthesized target compounds has been revealed using different analytical approaches such as FT-IR, LCMS, and NMR (proton and carbon), respectively. The in vitro carbonic anhydrase potentials of these synthesized 17 different analogues were investigated. The result suggests that compound 7g, a 3-pyridine substituted analogue with an IC50 of 0.1 µM, was found to have the most potent carbonic inhibitory activity (11-fold more active) than the positive control (acetazolamide) with an IC50 of 1.1 ± 0.1 µM. Besides, among the series 7(a-q) approved in the identification of four potent carbonic anhydrase inhibitors with the IC50 standards varies from 0.1 to 1.0 ± 0.1 µM. Additionally, the non-competitive behaviour for potent compound 7g was analysed using the Lineweaver-Burk plot from the kinetic study. Furthermore, the anticancer activity of all the synthesized compounds screened against B16F10 melanoma cells using the MTT assay method. Additionally, the molecular docking studies revealed that 7g inhibitor shows good binding energy as well as good binding interaction pattern along with enzyme.

Novel insight on IRE1 in the regulation of chondrocyte dedifferentiation through ER stress independent pathway.

Inositol-requiring enzyme-1 (IRE1) is the master regulator of the unfolded protein response pathway, associated with the endoplasmic reticulum (ER) in sensing and regulating cell stress. The activity of IRE1 is highly explored and well-characterized in cancer and other cells. However, the IRE1 molecular mechanism in chondrocytes is poorly understood. The present study explored the effect of IRE1 on chondrocytes regarding its chondrogenic gene expression and its correlation with different cellular pathways and cell behavior. Chondrocytes transfected with the cDNA of IRE1 reduced the expression of type II collagen, disrupting chondrocyte differentiation as confirmed by western blotting and immunofluorescence. Upon siRNA treatment, the influence of IRE1 on chondrocyte differentiation is restored by reviving the normal expression of type II collagen. Different molecular pathways were explored to investigate the role of IRE1 in causing chondrocyte dedifferentiation. However, we found no significant correlation, as IRE1 induces dedifferentiation through independent pathways. In response to various endoplasmic reticulum (ER) agonists (2-deoxy-D-glucose), and ER stress antagonists (tauroursodeoxycholic acid and salubrinal), IRE1 overexpression did not affect GRP78/94, as implicated in the pathogenesis of ER stress. Moreover, when IRE1 overexpression was correlated with the inflammation pathway, nuclear factor-kappa B (NFκB), IRE1 substantially increased the expression of p50 while decreasing the expression of nuclear factor kappa light polypeptide alpha (IκBα). These results suggest that IRE1 induces dedifferentiation in chondrocytes by modulating inflammatory pathways that cause dedifferentiation by disrupting type II collagen expression.

Evaluation of phytochemicals of Poria cocos against tyrosinase protein: a virtual screening, pharmacoinformatics and molecular dynamics study.

Tyrosinase inhibitors are commonly used in the pharmaceutical and cosmetic industries for skin lightening and hypopigmentation. The current inhibitors of tyrosinase induce strong safety concerns which necessitate the discovery of new inhibitors. Natural compounds are a promising solution to discover potential candidate for anti-melanogenic activity as they possess less safety concerns and high therapeutic effect. The current study aimed to screen and identify potential phytochemicals from Poria cocos for tyrosinase inhibition. The phytochemicals were obtained from the Traditional Chinese Medicine System Pharmacology Database and screened for druglikeness score and toxicity class and then subjected to in-silico virtual screening and molecular dynamics. 7,9-(11)-Dehydropachymic acid established hydrogen interaction with the tyrosinase protein and was found to be highly stable as validated with MD simulations. The pharmacokinetic results showed that this compound has adequate toxicity and ADME profile that can be exploited for anti-melanogenic effects. Our study identified 7,9-(11)-dehydropachymic acid as an efficient candidate for tyrosinase inhibition. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03626-8.

E3 Ubiquitin Ligase Constitutive Photomorphogenic 1 Regulates Differentiation and Inflammation via MAPK Signaling Pathway in Rabbit Articular Chondrocytes.

Constitutive photomorphogenic 1 (COP1), is an E3 ubiquitin ligase that plays a role in the regulation of various cellular processes including cell growth, differentiation, and survival in mammals. In certain conditions such as overexpression or loss of function, COP1 acts either as an oncogenic protein or as a tumor suppressor by targeting specific proteins for ubiquitination-mediated degradation. However, the precise role of COP1 has not been well studied in primary articular chondrocytes. In this study, we investigated the role of COP1 in chondrocyte differentiation. Western blotting and reverse transcription-polymerase chain reaction analysis demonstrated that COP1 overexpression reduced type II collagen expression, promoted cyclooxygenase 2 (COX-2) expression, and reduced sulfated proteoglycan synthesis, as detected by Alcian blue staining. Upon siRNA treatment, revived type II collagen, sulfated proteoglycan production, and decreased COX-2 expression. Phosphorylation of p38 kinase and ERK-1/-2 signaling pathways was regulated by COP1 upon cDNA and siRNA transfection in chondrocytes. The inhibition of the p38 kinase and ERK-1/-2 signaling pathways with SB203580 and PD98059 ameliorated the expression of type II collagen and COX-2 in transfected chondrocytes, thus suggesting that COP1 regulates differentiation and inflammation in rabbit articular chondrocytes via the p38 kinase and ERK-1/-2 signaling pathway.

Synthesis and discovery of potential tyrosinase inhibitor of new coumarin-based thiophenyl-pyrazolylthiazole nuclei: In vitro evaluation, cytotoxicity, kinetic, and computational studies.

A well-known key enzyme in melanogenesis and hyperpigmentation is tyrosinase. The present study introduces a novel series of thiophenyl-pyrazolylthiazole-coumarin hybrids (6a-6h) as tyrosinase inhibitors. The in-vitro tyrosinase inhibition results indicated that all compounds have strong tyrosinase inhibitory activity, particularly compound 6g (IC50  = 0.043 ± 0.006 µM), was identified as the most active compound compared to the positive control (kojic acid, IC50  = 18.521 ± 1.162 µM). Lineweaver-Burk plots were employed to analyze the kinetic mechanism, and compound 6g formed an enzyme-inhibitor complex by inhibiting tyrosinase non-competitively. Furthermore, all compounds demonstrated excellent antioxidant activity against DPPH. MTT assay was used to screen the cytotoxicity of all compounds on B16F10 melanoma cells, and they had no toxic effect on the cells. The binding affinity of compounds with tyrosinase was also investigated using molecular docking, and the ligands displayed good binding energy values. These molecules could be a promising lead for skin pigmentation and associated diseases as nontoxic pharmacological scaffolds.

Sulforaphane induces cell differentiation, melanogenesis and also inhibit the proliferation of melanoma cells.

Sulforaphane (SFN) is an organosulfur compound extracted from cruciferous vegetables and has biological effects. The effect of SFN has been studied in different types of cancers, as this compound incites various cytotoxic mechanisms to stunt cancer proliferation. However, the role of SFN activity in melanoma is yet to be known. The current study has been devised to elucidate the effects induced by SFN treatment in the B16F10 melanoma cell line and zebrafish model. Cells were treated with SFN reduced cell proliferation and increased tyrosinase production. Moreover, microscopic and immunofluorescence analysis confirmed the elongated appearance of melanoma cells due to cytoskeletal reorganization induced by SFN. Western blotting showed that SFN regulates the protein expression of Microphthalmia-associated transcription factor (MITF), Protein kinase C beta 1 (PKCß1), and tyrosinase. The relationship between melanin biosynthesis and changes in the actin cytoskeleton encouraged by SFN on melanoma was determined by treating it with Cytochalasin D (CD) and Jasplakinolide (JAS). Co-treatment of SFN with CD increased more tyrosinase expression than SFN alone whereas with JAS, slightly reduced the expression. Immature zebrafish were pretreated with phenylthiourea (PTU) and then exposed to different SFN concentrations yielded the same results by upregulating the melanin levels despite the presence of melanin inhibitor (PTU). These study results show that SFN induces the biosynthesis of melanin in the B16F10 melanoma cell line, which occurs through changes in actin.