Derivatives 2b Research Articles

Design, synthesis and cytotoxic evaluation of novel bis-thiazole derivatives as preferential Pim1 kinase inhibitors with in vivo and in silico study

Bis-thiazole derivatives were synthesised conforming to the Pim1 pharmacophore model following Hantzsch condensation. Pim1 has a major role in regulating the G1/S phase which upon inhibition the cell cycle stops at its early stages. Derivatives 3b and 8b showed the best Pim1 IC50 0.32 and 0.24 µM, respectively relative to staurosporine IC50 0.36 µM. Further confirmation of 3b and 8b Pim1 inhibition was implemented by hindering the T47D cell cycle at G0/G1 and S phases where 3b showed 66.5% cells accumulation at G0/G1 phase while 8b demonstrated 26.5% cells accumulation at the S phase compared to 53.9% and 14.9% of a control group for both phases, respectively. Additional in vivo cytotoxic evaluation of 3b and 8b revealed strong antitumor activity with up-regulation of caspase-3 and down-regulation of VEGF and TNF α immune expression with concomitant elevation of malondialdehyde levels in case of 8b.

Eco-friendly Synthesis of 2-Amino-4H-Chromene Catalysed by HRSPLAE and Anti-cancer Activity Studies

Background: Several types of catalysts have been cited in the literature. However, the current work showed that a multi-component reaction involving aldehydes, malononitrile, and resorcinol or α/β-naphthol could produce 2-amino-4H-chromene in a more environmentally friendly manner. The reaction is optimized by both stirring and microwave methods, but the reaction carried out under microwave irradiation is found to be faster with easy separation of the product with high yield and purity. The catalyst is analyzed for the presence of elemental composition using Flame Photometry (FP) and SEM-EDX. The synthesis of 2-amino-4H-chromenes is catalyzed by the new, green catalyst HRSPLAE (Water Extract of Hibiscus Rosa Sinensis plant dry leaves ash) within 3-5 min. The final product is analyzed by FT-IR, 1H-, 13C-NMR, and mass spectrometry techniques and the product obtained is free from the use of chromatographic separation with isolation and yield of 80–95%. Selected 2-amino-4H-chromene derivatives (4b and 4c) were screened for their anti-cancer and antimicrobial activity in vitro. Methods: The agro-waste sourced from Hibiscus rosa-sinensis plant dry leaves ash is utilized for the preparation of HRSPLAE catalyst, which is employed for the synthesis of 2-amino-4H-chromene derivatives under microwave irradiation. Results: 2-Amino-4H-chromene derivatives were obtained from aromatic aldehyde, malononitrile, and resorcinol or α/β naphthol catalyzed by HRSPLAE. They were comprehensively evaluated using flame emission spectrometry, SEM, and EDX. Conclusion: HRSPLAE outperforms expensive catalysts. An efficient simpler workup without column chromatography for increased yield through a new unique green method for the synthesis of 2-amino-4H-chromene derivatives has been developed.

Synthesis, ADMET Prediction, and Antitumor Profile of Phenoxyhydrazine- 1,3-thiazoles Derivatives.

Cancer is one of the most important barriers to increasing life expectancy in all countries in the 21st century. Investigations of new anti-cancer drugs with low side effects are an urgent demand for medicinal chemists. Considering the known antitumor and immunomodulatory activity of thiazoles, this work presents the synthesis and antineoplastic activity of new thiazoles. The 22 new compounds (2a-v) were synthesized from different thiosemicarbazones and 2-bromoacetophenone. The compounds were evaluated on: MOLT-4, HL-60, HL-60/MX1, MM1S, SKMEL-28, DU145, MCF-7, and T47d. Compound 2b induced cellular viability on MOLT-4 (37.1%), DU145 (41.5%), and HL- 60/MX1 (58.8%) cells. On MOLT-4 cells, compound 2b exhibited an IC50 of 8.03 μM, and against DU145 cells, an IC50 of 6.04μM. Besides, at IC50 and fold of IC50, 20% to 30% of dead cells were found, most due to necrosis/late apoptosis. Most compounds no showed cytotoxicity against fibroblast cells L929 at the concentrations tested. The compound did not alter the cell cycle of DU145 cells when compared to the negative control. Therefore, compound 2b stands out against DU145 and MOLT-4 cells. Our study reinforced the importance of 1,3-thiazoles nuclei in antitumor activity. In addition, derivative 2b stands out against DU145 and MOLT-4 cells and could be a starting point for developing new antineoplastic agents.

Semisynthetic Sesquiterpene Lactones Generated by the Sensibility of Glaucolide B to Lewis and Brønsted-Lowry Acids and Bases: Cytotoxicity and Anti-Inflammatory Activities.

Sesquiterpene lactone (SL) subtypes including hirsutinolide and cadinanolide have a controversial genesis. Metabolites of these classes are either described as natural products or as artifacts produced via the influence of solvents, chromatographic mobile phases, and adsorbents used in phytochemical studies. Based on this divergence, and to better understand the sensibility of these metabolites, different pH conditions were used to prepare semisynthetic SLs and evaluate the anti-inflammatory and antiproliferative activities. Therefore, glaucolide B (1) was treated with various Brønsted-Lowry and Lewis acids and bases-the same approach was applied to some of its derivatives-allowing us to obtain 14 semisynthetic SL derivatives, 10 of which are hereby reported for the first time. Hirsutinolide derivatives 7a (CC50 = 5.0 µM; SI = 2.5) and 7b (CC50 = 11.2 µM; SI = 2.5) and the germacranolide derivative 8a (CC50 = 3.1 µM; SI = 3.0) revealed significant cytotoxic activity and selectivity against human melanoma SK-MEL-28 cells when compared with that against non-tumoral HUVEC cells. Additionally, compounds 7a and 7c.1 showed strongly reduced interleukin-6 (IL-6) and nitrite (NOx) release in pre-treated M1 macrophages J774A.1 when stimulated with lipopolysaccharide. Despite the fact that hirsutinolide and cadinanolide SLs may be produced via plant metabolism, this study shows that acidic and alkaline extraction and solid-phase purification processes can promote their formation.

Design, synthesis and biological activity of hybrid antifungals derived from fluconazole and mebendazole

A novel series of triazole alcohol antifungals bearing a 5-benzoylbenzimidazol-2-ylthio side chain have been designed and synthesized as hybrids of fluconazole (a typical triazole antifungal) and mebendazole (an anthelmintic agent with antifungal activity). The title compounds were synthesized via the reaction of an appropriate oxirane and desired 2-mercaptobenzimidazole. Although there was possibility for formation of different N-substituted or S-substituted products, the structures of final compounds were assigned as thioether congeners by using 13C NMR spectroscopy. The SAR analysis of the primary lead compounds (series A) was conducted by simplifying the 5-benzoylbenzimidazol-2-ylthio residue to the benzimidazol-2-ylthio (series B) or benzothiazol-2-ylthio side chain (series C), and modification of halogen substituent on the phenethyl-triazole scaffold. In general, series A (compounds 4a-e) containing 5-benzoylbenzimidazole scaffold showed better antifungal activity against Candida spp. and Cryptococcus neoformans than related benzimidazole and benzothiazole derivatives. The better results were obtained with the 4-chloro derivative 4b displaying MICs <0.063–1 μg/mL. Although, removing benzoyl group from compound 4b had negative effect on the activity, optimization of phenethyl-triazole scaffold by desired halogen substituent resulted in compound 5c being as potent as 4b. In vitro and in silico ADMET evaluations of the most promising compounds 4b and 5c indicated that the selected compounds have desirable ADMET properties in comparison to standard drug fluconazole. Docking simulation study demonstrated that the benzimidazol-2-ylthio moiety is responsible for the potent antifungal activity of these compounds.

Synthesis of new 1,2,3-triazole linked benzimidazolidinone: Single crystal X-ray structure, biological activities evaluation and molecular docking studies

A novel series of 1,2,3-triazole-benzimidazolidinone hybrid derivatives were designed and synthesized via click reaction, between various aryl azide and a terminal alkyne bearing a benzimidazolidinone moiety. All newly synthesized compounds, were efficiently characterized using 1H NMR, 13C NMR and HRMS. Furthermore, the structure of one precursor 5b was supported by single crystal X-ray diffraction. All synthesized derivatives have been evaluated for their antimicrobial and anti-inflammatory activities. Biological activity tests exhibited that the target structures demonstrate that compounds 5a, 5b and 5f have a high antibacterial activity especially derivative 5b. Besides, the in vitro antifungal results revealed that the strongest inhibition recorded to compound 5b in comparison to other products against A. brasiliensis, A. fumigatus and C. albicans. Biological activity evaluation indicated that the synthesized compounds possess moderate anti-inflammatory effects. The most effective compound in terms of efficacy and potency was 5a. Molecular docking simulation was used to investigate the most active compounds' probable binding mechanisms in order to provide a plausible explanation for their biological activity.

Synthesis and Molecular Docking of Some Novel 3-Thiazolyl-Coumarins as Inhibitors of VEGFR-2 Kinase.

One crucial strategy for the treatment of breast cancer involves focusing on the Vascular Endothelial Growth Factor Receptor (VEGFR-2) signaling system. Consequently, the development of new (VEGFR-2) inhibitors is of the utmost importance. In this study, novel 3-thiazolhydrazinylcoumarins were designed and synthesized via the reaction of phenylazoacetylcoumarin with various hydrazonoyl halides and α-bromoketones. By using elemental and spectral analysis data (IR, 1H-NMR, 13C-NMR, and Mass), the ascribed structures for all newly synthesized compounds were clarified, and the mechanisms underlying their formation were delineated. The molecular docking studies of the resulting 6-(phenyldiazenyl)-2H-chromen-2-one (3, 6a-e, 10a-c and 12a-c) derivatives were assessed against VEGFR-2 and demonstrated comparable activities to that of Sorafenib (approved medicine) with compounds 6d and 6b showing the highest binding scores (-9.900 and -9.819 kcal/mol, respectively). The cytotoxicity of the most active thiazole derivatives 6d, 6b, 6c, 10c and 10a were investigated for their human breast cancer (MCF-7) cell line and normal cell line LLC-Mk2 using MTT assay and Sorafenib as the reference drug. The results revealed that compounds 6d and 6b exhibited greater anticancer activities (IC50 = 10.5 ± 0.71 and 11.2 ± 0.80 μM, respectively) than the Sorafenib reference drug (IC50 = 5.10 ± 0.49 μM). Therefore, the present study demonstrated that thiazolyl coumarins are potential (VEGFR-2) inhibitors and pave the way for the synthesis of additional libraries based on the reported scaffold, which could eventually lead to the development of efficient treatment for breast cancer.

Structure-activity relationship study to improve cytotoxicity and selectivity of lonafarnib against breast cancer cells.

Lonafarnib is designed as a farnesyltransferase (FTase) inhibitor and displays inhibitory activities against a wide range of tumor cells. However, a major disadvantage is its unselective activity and high cytotoxicity against nonmalignant cells. Therefore, we structurally modified the terminal 4-methylpiperidine-1-carboxamide residue of lonafarnib and evaluated the antiproliferative effects of the resulting derivatives in Michigan Cancer Foundation - 7 (MCF-7) breast cancer cells as well as simian virus 80 (SV-80) fibroblasts. The highest cytotoxicity against both cell lines (IC50 about 2 µM) was shown by the piperidin-4-yl carbamate 15i and the S-(piperidin-4-yl) carbamothioate 15j. Selectivity for tumor cells was realized in the case of the 1-cyclohexyl-1-methylurea derivative 15b. It reduced the growth of MCF-7 cells with an IC50 of 11.4 µM (lonafarnib: IC50 = 10.8 µM) without influence on the growth of SV-80 cells (IC50 > 50 µM; lonafarnib: IC50 = 14.0 µM). Molecular modeling studies were performed to correlate the cytotoxicity with possible FTase interactions. The theoretical investigations, however, documented a comparable attachment of active, less active, and inactive compounds and did not allow an interpretation of the biological results based on these theoretical considerations.

Seleno-Analogs of Scaffolds Resembling Natural Products a Novel Warhead toward Dual Compounds.

Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer's disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD50 values below 9.2 µM. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 × 10-6 cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.

Synthesis and Anticancer Evaluation of New Indole-Based Tyrphostin Derivatives and Their (p-Cymene)dichloridoruthenium(II) Complexes.

New N-alkylindole-substituted 2-(pyrid-3-yl)-acrylonitriles with putative kinase inhibitory activity and their (p-cymene)Ru(II) piano-stool complexes were prepared and tested for their antiproliferative efficacy in various cancer models. Some of the indole-based derivatives inhibited tumor cell proliferation at (sub-)micromolar concentrations with IC50 values below those of the clinically relevant multikinase inhibitors gefitinib and sorafenib, which served as positive controls. A focus was set on the investigation of drug mechanisms in HCT-116 p53-knockout colon cancer cells in order to evaluate the dependence of the test compounds on p53. Colony formation assays as well as experiments with tumor spheroids confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic caspase-3/7 activity and ROS formation, as well as anti-angiogenic properties. Docking calculations with EGFR and VEGFR-2 identified the two 3-aryl-2-(pyrid-3-yl)acrylonitrile derivatives 2a and 2b as potential kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in cancer treatment.

Novel fluorinated pyrazole-based heterocycles scaffold: cytotoxicity, in silico studies and molecular modelling targeting double mutant EGFR L858R/T790M as antiproliferative and apoptotic agents

Hepatocellular carcinoma (HCC), also known as hepatoma, is the most prevalent type of primary liver cancer. It begins in the hepatocytes, the liver’s major cell type. Cancer that began in another region of the body but has spread to the liver is known as secondary cancer of life; several still unmet demands for better, less toxic therapy to treat this malignant tumor. Several novel pyrazolo[1,5-a]pyrimidine derivatives were synthesized as part of our goal to develop promising anticancer drugs. All the synthesized hybrids have been screened for their cytotoxicity effect against three cancer cell lines which are; HepG-2, HCT-116, and MCF-7. The liver cancer cells were found to be the most sensitive to the effect of the new molecules. A subsequent set of in vitro biological evaluation studies has been conducted on the most promising derivatives to identify their effect on such a cancer type. In HepG-2 cells, four derivatives (8a, 8b, 10c, and 11b) demonstrated good anticancer activity. The most efficacious compounds were 8b and 10c, which had IC50 values of 2.36 ± 0.14 and 1.14 ± 0.063 μM, respectively, higher than the reference medication Imatinib. The latter’s putative molecular effect has been investigated further by looking at its influence on the cell cycle, EGFR, and specific apoptotic and anti-apoptotic markers in HepG-2 cells. These findings indicated that 8b and 10c could trigger apoptosis by upregulating BAX and caspase-3 and cell cycle at the Pre-G1 and G2-M stages. The compounds 8b and 10c showed high potency for EGFR with IC50 equal to 0.098 and 0.079 μM, respectively. Compound 10c had the most effective inhibitory activity for EGFR L858R-TK with IC50 (36.79 nM). Additionally, in silico ADMET and docking studies were done for the most active hits, representing good results.Graphical Novel Fluorinated Pyrazole-Based Heterocycles Scaffold: Cytotoxicity, In Silico Studies and Molecular Modelling Targeting Double Mutant EGFR L858R/T790M as Antiproliferative and Apoptotic Agents

New 1,3,4-thiadiazoles as potential anticancer agents: pro-apoptotic, cell cycle arrest, molecular modelling, and ADMET profile.

A series of novel 1,3,4-thiadiazoles was synthesized via the reaction of N-(5-(2-cyanoacetamido)-1,3,4-thiadiazol-2-yl)benzamide (3) with different carbon electrophiles and evaluated as potential anticancer agents. The chemical structures of these derivatives were fully elucidated using various spectral and elemental analyses. Out of 24 new thiadiazoles, derivatives 4, 6b, 7a, 7d, and 19 have significant antiproliferative activity. However, derivatives 4, 7a, and 7d were toxic to the normal fibroblasts, and therefore were excluded from further investigations. Derivatives 6b and 19 with IC50 at less than 10 μM and with high selectivity were selected for further studies in breast cells (MCF-7). Derivative 19 arrested the breast cells at G2/M probably through inhibition of CDK1, while 6b significantly increased the sub-G1 percent of cells probably through induction of necrosis. These results were confirmed by the annexin V-PI assay where 6b did not induce apoptosis and increased the necrotic cells to 12.5%, and compound 19 significantly increased the early apoptosis to 15% and increased the necrotic cells to 15%. Molecular docking showed that compound 19 was like FB8, an inhibitor of CDK1, in binding the CDK1 pocket. Therefore, compound 19 could be a potential CDK1 inhibitor. Derivatives 6b and 19 did not violate Lipinski's rule of five. In silico studies showed that these derivatives have a low blood-brain barrier penetration capability and high intestinal absorption. Taken together, derivatives 6b and 19 could serve as potential anticancer agents and merit further investigations.

Synthesis of 2-aminopropyl benzopyran derivatives as potential agents against triple-negative breast cancer.

Synthesis of three series of 2-aminopropyl derivatives containing a benzopyran nucleus was performed to evaluate their performance against triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-436) and normal breast epithelial cells (MCF10A). For the three series, the cytotoxic activity was as follows: N-methylated derivatives (tertiary amines) 5b, 6b, and 7b > secondary amine benzopyrans 5, 6, and 7 > quaternary amine salts 5c, 6c, and 7c > free phenolic derivatives 5a, 6a, and 7a. The structure-activity relationship showed the importance of the presence of an amine group and a p-fluorobenzyloxy substituent in the chromanol ring (IC50 values from 1.5 μM to 58.4 μM). In addition, 5a, 5b, 6a, and 7b displayed slight selectivity towards tumor cells. Compounds 5, 5a, 5b, 6, 6a, 6c, 7, and 7b showed apoptotic/necrotic effects due to, at least in part, an increase in reactive oxygen species generation, whereas 5b, 5c, 6b, 7a, and 7c caused cell cycle arrest in the G1 phase. Further cell-based mechanistic studies revealed that 5a, 6a, and 7b, which were the most promising compounds, downregulated the expression of Bcl-2, while 5b downregulated the expression of cyclins CCND1 and CCND2. Therefore, 2-aminopropyl benzopyran derivatives emerge as new hits and potential leads for developing useful agents against breast cancer.

Thiazolo[5,4-d]thiazoles with a spirobifluorene moiety as novel D–π–A type organic hosts: design, synthesis, structure–property relationship and applications in electroluminescent devices

Novel D–π–A type organic small-molecules with thiazolo[5,4-d]thiazole and spirobifluorene units. Optoelectronical properties suggests their applications in materials. Electroluminescent devices containing the novel TzTz-based derivatives 4b, 5b show affinitive emission.

Synthesis and anti-inflammatory activity of S-oxides of pyridinyloxy substituted imidazo[2,1-b][1,3]thiazines

Here derivatives of imidazo[2,1-b][1,3]thiazines are attractive objects for organic and medicinal chemists. In the present work chemoselective conditions for oxidation of the sulfur atom in the 6-(2-pyridinyloxy)substituted (benzo)imidazo[2,1-b][1,3]thiazines to the corresponding sulfoxides were proposed and their synthesis was performed. Synthesized sulfoxides exist in the diastereomeric mixture and individual diastereomers 2a-e and 3a-e were obtained using a chromatographic technique. The structure of compounds 2a-e and 3a-e were characterized using 1H, 13C NMR, LC-MS spectra, and X-ray analysis for derivative 2b. The anti-inflammatory activity screening in vivo was performed using the carrageenan model of inflammatory paw edema in white rats for all the diastereomeric mixtures and individual diastereomers. Diastereomer 2c possessed an anti-inflammatory effect with an inflammation inhibition index of 46.1% which was equal to the activity of the reference drug diclofenac sodium.

Novel Semisynthetic Betulinic Acid−Triazole Hybrids with In Vitro Antiproliferative Potential

Betulinic acid, BA, is a lupane derivative that has caught the interest of researchers due to the wide variety of pharmacological properties it exhibits towards tumor cells. Because of their prospective increased anti−proliferative efficacy and improved pharmacological profile, BA derivatives continue to be described in the scientific literature. The current work was conducted in order to determine the antiproliferative activity, under an in vitro environment of the newly developed 1,2,4−triazole derivatives of BA. The compounds and their reaction intermediates were tested on three cancer cell lines, namely RPMI−7951 human malignant melanoma, HT−29 colorectal adenocarcinoma, A549 lung carcinoma, and healthy cell line (HaCaT human keratinocytes). BA−triazole derivatives 4a and 4b revealed lower IC50 values in almost all cases when compared to their precursors, exhibiting the highest cytotoxicity against the RPMI−7951 cell line (IC50: 18.8 μM for 4a and 20.7 μM for 4b). Further biological assessment of these compounds executed on the most affected cell line revealed a mitochondrial level induced apoptotic mechanism where both compounds inhibited mitochondrial respiration in RPMI−7951 cells. Furthermore, the triazole−BA derivatives caused a significant decrease of the anti−apoptotic Bcl−2 gene expression, while increasing the pro−apoptotic BAX gene’s expression.

Evaluation of Anti-inflammatory Activity of Novel HDAC Inhibitors using in vitro Methods

Inflammation is a neighborhood reaction to cell injury that is set apart by fine enlargement, leukocytic invasion, redness, heat, agony, expanding and loss of function. HDAC inhibitors play crucial role in regulation of inflammatory gene expression. The point of the investigation was to assess the anti-inflammatory activity of novel HDAC inhibitors having cinnamyl moiety. In the present study, two cinnamyl sulfonamide hydroxamate (CSH) derivatives (4a and 4b) were evaluated for their anti-inflammatory activity by in vitro methods, includes COX, LOX inhibitory assay, iNOS, MPO and determination of cellular nitrite level. The present study revealed that the newly derived compound 4a have potential anti-inflammatory activity and can serves as lead molecule in drug discovery.

Synthesis and Pharmacological Evaluation of Novel Quinazoline Derivatives as Potential EGFR Inhibitors for Breast Cancer

Background: Breast cancer is the highest mortality-causing disease among cancers in women and it can be cured by early diagnosis as well as treatment. Epidermal growth factor receptor-2 (HER2) is the prime factor that helps in the growth and development of breast cancer. There are several EGFR inhibitors approved for breast cancer treatment, but all are shown to cause resistance and severe toxicity. The present research work is based on the synthesis and pharmacological evaluation of novel derivatives against breast cancer cell lines. Materials and Methods: Ten novel Quinazoline derivatives (4a-j) were synthesized and characterized by IR, PMR, and CMR spectroscopic methods. Cell proliferation and cytotoxic effects of synthesized derivatives were determined by using MTT assay and hemolytic assay. Results: The growth inhibition potential of synthesized derivatives was evaluated against normal as well as mutated breast cancer cell lines i.e., MCF-7 and MDA-MB-231 using the MTT method. Nearly, five derivatives 4b, 4c, 4e, 4f, 4i for MCF-7 and 4b, 4c, 4d, 4e, 4f, 4i for MDA-MB231 were assessed for IC50 value. It was observed that these compounds of the series exhibited higher IC50 values (8.72 to 15.70, 12.66 to 21.21μM/mL) as compared to erlotinib with IC50 values (16.80, 22.80), respectively. Moreover, the hemolytic estimation of the derivatives (4e, 2-Br) and (4i 4-CN) displayed less toxicity with HD50 values 69.87±8.9, 58.40±3.2, respectively. Conclusion: The findings of the current study provide safe, less-toxic, cost-effective, and potent novel quinazoline derivatives for breast cancer.

Diversity and antibacterial potential of the Actinobacteria associated with Apis mellifera ligustica.

Insect-associated Actinobacteria are a potentially rich source of novel natural products with antibacterial activity. Here, the community composition of Actinobacteria associated with Apis mellifera ligustica was investigated by integrated culture-dependent and independent methods. A total of 61 strains of Streptomyces genera were isolated from the honeycomb, larva, and different anatomical parts of the honeybee's body using the culture-dependent method. Amplicon sequencing analyses revealed that the actinobacterial communities were dominated by the family of Bifidobacteriaceae and Microbacteriaceae in the honeybee gut, and Nocardiaceae and Pseudonocardiaceae in the honeycomb, whereas only Streptomyces genera were isolated by the culture-dependent method. Culture-independent analyses showed more diverse actinobacterial communities than those of culture-dependent methods. The antibacterial bioassay showed that most crude extracts of representative isolates exhibited antibacterial activities. Among them, the crude extract of Streptomyces sp. FCF01 showed the best antibacterial activities against Staphylococcus aureus, Micrococcus tetragenus, and Pseudomonas syringae pv. actinidiae (Psa) with the disc diameter of inhibition zone diameter (IZD) of 23.00, 15.00, and 13.33 mm, respectively. Chemical analysis of Streptomyces sp. FCF01 led to the isolation of three secondary metabolites, including mayamycin (1), mayamycin B (2), and N-(2-Hydroxyphenyl) acetamide (3). Among them, compound 1 displayed strong antibacterial activity against S. aureus, M. tetragenus, and Psa with minimum inhibitory concentrations (MIC) values of 6.25, 12.5, and 6.25 μg/ml, respectively. In addition, two novel derivative compounds 1a and 1b were synthesized by acetylation of compound 1. Both compounds 1a and 1b displayed similar antibacterial activities with those of metabolite 1. These results indicated that Streptomyces species associated with honeybees had great potential in finding antibiotics.

Chalcone derivatives as xanthine oxidase inhibitors: synthesis, binding mode investigation, biological evaluation, and ADMET prediction

Xanthine oxidase (XO) is a crucial target for the treatment of hyperuricemia and gout. A series of derivatives based on natural 3,4-dihydroxychalcone, obtained from Carthamus tinctorious and Licorice, were designed and synthesized. Nine derivatives (9a-e, 10b,c, and 15a,b) exhibited apparent XO inhibitory activity in vitro (IC50 values varied from 0.121 to 7.086 μM), 15b presented the most potent inhibitory activity (IC50 = 0.121 µM), which was 27.47-fold higher than that of allopurinol (IC50 = 3.324 µM). The SAR analysis indicated that introducing hydroxyl groups at 3′/4′/5′-position on ring A was more beneficial to the inhibition of XO than at 2′/6′-position; the removal of 3‑hydroxyl group on ring B could weaken the inhibitory potency of hydroxychalcones on XO, but it was beneficial to the XO inhibitory potency of methoxychalcones. Molecule modeling studies afforded insights into the binding mode of 15b with XO and supported the findings of SAR analysis. Additionally, kinetics studies demonstrated that 15b presented a reversible and competitive XO inhibitor, which spontaneously combined with XO through hydrophobic force, and finally changed the secondary conformation of XO. Furthermore, the acute hyperuricemia model was employed to investigate the hypouricemic effect of 15b, which could effectively reduce the serum uric acid levels of rats at an oral dose of 10 mg/kg. ADMET prediction suggested that compound 15b possessed good pharmacokinetic properties. Briefly, compound 15b emerges as an interesting XO inhibitor for the treatment of hyperuricemia and gout with beneficial effects on serum uric acid levels regulating. Meanwhile, the XO inhibitors with chalcone skeleton will deserve further attention and discussion.