Design,synthesis, molecular docking,and anticancer evaluations of 1-benzylquinazoline-2,4(1H,3H)-dione bearing different moieties as VEGFR-2 inhibitors

A novel series of 1-benzylquinazoline-2,4(1H,3H)-dione derivatives, 6a , b to 11a – e , was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT-116, and MCF-7 cells. Compounds 11b , 11e , and 11c were found to be the most potent derivatives of all tested compounds against the HepG2, HCT-116, and MCF-7 cancer cell lines, with GI₅₀ = 9.16 ± 0.8, 5.69 ± 0.4, 5.27 ± 0.2 µM, 9.32 ± 0.9, 6.37 ± 0.7, 5.67 ± 0.5 µM, and 9.39 ± 0.5, 6.87 ± 0.7, 5.80 ± 0.4 µM, respectively. These compounds exhibited nearly the same activity as sorafenib against HepG2 and HCT-116 cells and a higher activity against MCF-7 cells (GI₅₀ = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). Also, these compounds displayed a lower activity than doxorubicin against HepG2 cells and a higher activity against HCT-116 and MCF-7 cells (GI₅₀ = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively). The most active antiproliferative derivatives, 6a , b , 8 , 9 , and 11a – e , were selected to evaluate their enzymatic inhibitory activity against VEGFR-2. Compounds 11b , 11e , and 11c potently inhibited VEGFR-2 at IC₅₀ values of 0.12 ± 0.02, 0.12 ± 0.02, and 0.13 ± 0.02 µM, respectively, which are nearly equipotent as sorafenib IC₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.     

Design,synthesis, docking,and anticancer evaluations of phthalazines as VEGFR-2 inhibitors

Twenty new N-substituted-4-phenylphthalazin-1-amine derivatives were designed, synthesized, and evaluated for their anticancer activities against HepG2, HCT-116, and MCF-7 cells as VEGFR-2 inhibitors. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 7f was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, with 50% inhibition concentration, IC₅₀ = 3.97, 4.83, and 4.58 µM, respectively, which is more potent than both sorafenib (IC₅₀ = 9.18, 5.47, and 7.26 µM, respectively) and doxorubicin (IC₅₀ = 7.94, 8.07, and 6.75 µM, respectively). Fifteen of the synthesized derivatives were selected to evaluate their inhibitory activities against VEGFR-2. Compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC₅₀ value of 0.08 µM, which is more potent than sorafenib (IC₅₀ = 0.10 µM). Compound 8c inhibited VEGFR-2 at an IC₅₀ value of 0.10 µM, which is equipotent to sorafenib. Moreover, compound 7a showed very good activity with IC₅₀ values of 0.11 µM, which is nearly equipotent to sorafenib. In addition, compounds 7d , 7c , and 7g possessed very good VEGFR-2-inhibitory activity, with IC₅₀ values of 0.14, 0.17, and 0.23 µM, respectively.     

Benzoxazole/benzothiazole‐derived VEGFR‐2 inhibitors: Design,synthesis, molecular docking,and anticancer evaluations

A novel series of benzoxazole/benzothiazole derivatives 4a–c – 11a–e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT‐116, and MCF‐7 cells, with IC₅₀ values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f , and 9c showed the highest anticancer activities against HepG2 cells with IC₅₀ values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT‐116 cells with IC₅₀ values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF‐7 cells with IC₅₀ values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC₅₀ values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a–c, 9b,c,e,f,h , and 11c,e were further evaluated for their VEGFR‐2 inhibition. Compounds 4c and 4b potently inhibited VEGFR‐2 at IC₅₀ values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.     

Design,synthesis, molecular docking,and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors

Novel series of benzoxazole s 4 _a‐f ‐16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 _e was found to be the most potent against HepG2, HCT‐116, and MCF‐7 with IC₅₀ = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5 _c , 5 _f , 6 _b , 5 _d , and 6 _c showed the highest anticancer activities against HepG2 cells with IC₅₀ of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT‐116 cells with IC₅₀ of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF‐7 cells with IC₅₀ of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC₅₀ of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5 _c‐f and 6 _b,c were further evaluated for their vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibition. Compounds 5 _e and 5 _c potently inhibited VEGFR‐2 at lower IC₅₀ values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC₅₀ = 0.1 ± 0.02 µM). Compound 5 _f potently inhibited VEGFR‐2 at low IC₅₀ value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR‐2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.     

Design,synthesis, and molecular docking of novel indole scaffold‐based VEGFR‐2 inhibitors as targeted anticancer agents

A series of new indole derivatives 1 – 18 was synthesized and tested for their cytotoxic activity on a panel of 60 tumor cell lines. Additionally, molecular docking was carried out to study their binding pattern and binding affinity in the VEGFR‐2 active site using sorafenib as a reference VEGFR‐2 inhibitor. Based on the molecular docking results, compounds 5a , 5b , 6 , 7 , 14b , 18b , and 18c were selected to be evaluated for their VEGFR‐2 inhibitory activity. Compound 18b exhibited a broad‐spectrum antiproliferative activity on 47 cell lines, with GI % ranging from 31 to 82.5%. Moreover, compound 18b was the most potent VEGFR‐2 inhibitor with an IC₅₀ value of 0.07 μM, which is more potent than that of sorafenib (0.09 μM). A molecular docking study attributed the promising activity of this series to their hydrophobic interaction with the VEGFR‐2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and/or Asp1046.

     

Novel 1,2,4-triazole derivatives: Design,synthesis, anticancer evaluation,molecular docking,and pharmacokinetic profiling studies

Three novel series of 1,2,4-triazole derivatives were designed and synthesized as potential adenosine A2B receptor antagonists. The design of the new compounds depended on a virtual screening of a previously constructed library of compounds targeting the human adenosine A2B protein. Spectroscopic techniques including ¹H nuclear magnetic resonance (NMR) and ¹³C NMR, and infrared and mass spectroscopy were used to confirm the structures of the synthesized compounds. The in vitro cytotoxicity evaluation was carried out against a human breast adenocarcinoma cell line (MDA-MB-231) using the MTT assay, and the obtained results were compared with doxorubicin as a reference anticancer agent. In addition, in silico studies to propose how the two most active compounds interact with the adenosine A2B receptor as a potential target were performed. Furthermore, a structure–activity relationship analysis was performed, and the pharmacokinetic profile to predict the oral bioavailability and other pharmacokinetic properties was also explained. Four of our designed derivatives showed promising cytotoxic effects against the selected cancer cell line. Compound 15 showed the highest activity with an IC₅₀ value of 3.48 µM. Also, compound 20 revealed an equipotent activity with the reference cytotoxic drug, with an IC₅₀ value of 5.95 µM. The observed IC₅₀ values were consistent with the obtained in silico docking scores. The newly designed compounds revealed promising pharmacokinetic profiles as compared with the reference marketed drug.     

VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016)

Introduction: Angiogenesis is an important component of certain normal physiological processes, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth. Activation of vascular endothelial growth factor receptor-2 (VEGFR-2) by vascular endothelial growth factor (VEGF) is a critical step in the signal transduction pathway that initiates tumor angiogenesis. Inhibition of angiogenesis via blocking VEGF/VEGFR-2 signaling pathway has emerged as a potential approach to anticancer therapy. Indeed, this approach has recently been clinically validated with the approvals of VEGFR-2 inhibitors.

Areas covered: This review accounts for small-molecule inhibitors and antibodies of VEGFR-2 reported in the patent literature covering between January 2012 and June 2016, and their potential use as therapeutics for cancers, angiogenesis-related disorders and inflammatory diseases.

Expert opinion: Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach. VEGF expression levels can be elevated by numerous diverse stimuli such as the activation of other RTK signaling transduction pathway. Therefore, the development of multi-targeted tyrosine kinase inhibitors and the strategy of using these agents in conjunction with other anti-cancer agents are recent interesting therapeutic approaches that could give promising results.     

Synthesis and antibacterial activity of new (2,4-dioxothiazolidin-5-yl/ylidene)acetic acid derivatives with thiazolidine-2,4-dione,rhodanine and 2-thiohydantoin moieties

A series of new (2,4-dioxothiazolidin-5-yl/ylidene)acetic acid derivatives with thiazolidine-2,4-dione, rhodanine and 2-thiohydantoin moiety (28–65) were synthesized by the reaction of (2,4-dioxothiazolidin-5-yl/ylidene)acetic acid chlorides with 5-(hydroxybenzylidene) thiazolidine-2,4-dione, rhodanine and 2-thiohydantoin derivatives. Obtained compounds (28–65) were tested on reference strains of Gram-positive bacteria and ones of the Gram-negative bacteria. The antibacterial activity of target compounds was determined by broth microdilution method. These derivatives showed antibacterial activity generally against Gram-positive bacterial strains. Most active compounds possess MIC?=?3.91?mg/L. Our results suggest that presence of electron-withdrawing substituent at phenyl ring is favorable while geometry of molecule does not play important role in antibacterial response. It was confirmed the lack of direct influence of substitution pattern at phenyl ring on antibacterial activity of closely related compounds of series 1–3. The antibacterial activity of some compounds was similar or higher than the activity of commonly used reference drugs such as oxacillin and cefuroxime.     

Regioselective synthesis,biological evaluation,and molecular docking of dihydropyrimidin‐4‐ols as acetylcholinesterase inhibitors

A new series of 3,6‐disubstituted 2‐(methylthio)‐4‐(trifluoromethyl)‐3,4‐dihydropyrimidin‐4‐ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6‐position; and methyl, ethyl, allyl, and phenyl groups at the 3‐position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase inhibitory activity. Seven compounds showed activity with IC₅₀ values in the lower micromolar range. The compound 4‐trifluoromethyl‐6‐(4‐fluorophenyl)‐3‐methyl‐2‐methylthio‐3,4‐dihydropyrimidin‐4‐ol ( 6e ) had the best inhibitory activity (IC₅₀ 2.2 ± 0.9 μm ) and this inhibition was characterized as competitive. The molecular docking study showed that the acetylcholinesterase enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e , present similar interactions: π–π stacking interactions between the aromatic ring of the ligand's 4‐fluorophenyl moiety and the aromatic rings of the electron‐rich Trp84; and H‐bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e . The antioxidant effect of the dihydropyrimidin‐4‐ols was also investigated.     

Design,synthesis, and molecular docking of novel 2-arylbenzothiazole multiangiokinase inhibitors targeting breast cancer

A novel series of 2-arylbenzothiazoles 9, 10 , and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-β multiangiokinase inhibitors targeting breast cancer. Structural elongation of the known 2-phenylbenzothiazole scaffold (type I protein kinase inhibitor [PKI]), was carried out to afford series of type II PKIs 9, 10 , and 12 . Compounds 9d, 9f, 9i , and 9k exhibited potent multikinase inhibitory activity with IC₅₀ values of 0.19, 0.18, 0.17, and 0.13 μM, respectively, against VEGFR-2; IC₅₀ values of 0.28, 0.37, 0.19, and 0.27 μM, respectively, against FGFR-1; and IC₅₀ values of 0.07, 0.04, 0.08, and 0.14 μM, respectively, against PDGFR-β. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC₅₀ values of 7.83 and 6.58 μM, respectively, on the MCF-7 cell line in comparison to sorafenib ( III ), which showed IC₅₀ = 4.33 μM. Additionally, 9d and 9i showed VEGFR-2 inhibitory activity in MCF-7 cells of 81% and 83% when compared with sorafenib ( III ), which showed 88% inhibition. Molecular docking of the designed compounds in the VEGFR-2 and FGFR-1 active sites showed the accommodation of the 2-phenylbenzothiazole moiety, as reported, in the hinge region of the receptor tyrosine kinase (RTK)-binding site, while the amide moiety is involved in hydrogen bond interactions with the key amino acids in the gate area; this in turn directs the aryl group to the hydrophobic allosteric back pocket of the RTKs in a type II-like binding mode. The synthesized benzothiazoles showed satisfactory ADME properties for further optimization in drug discovery.     

Design,synthesis, and molecular docking studies of novel quinoxaline derivatives as anticancer agents

As lung cancer was placed foremost part among other types of cancer in terms of mortality. Recent researches are widely focused on developing multi-targeted and site-specific targeted drug designs. In the present study, we designed and developed a series of quinoxaline pharmacophore derivatives as active EGFR inhibitors for the treatment of non-small cell lung cancer. The compounds were synthesized through a condensation reaction between hexane-3,4-dione and methyl 3,4-diaminobenzoate as a first step. Their structures were confirmed by ¹H-NMR, ¹³C-NMR, and HRMS spectroscopic methods. Cytotoxicity (MTT) were applied to determine anticancer activity of the compounds against breast (MCF7), fibroblast (NIH3 T3), and lung (A549) cell lines as EGFR inhibitors. Doxorubicin was used as a reference agent, compound 4i exhibited a significant effect among other derivatives with IC₅₀ = 3.902 ± 0.098 μM value against A549 cell line. The docking study showed that the best position on EGFR receptor could be observed with 4i . From the obtained evaluations of the designed series, compound 4i was a promising agent as EGFR inhibitor for further investigation and evaluation studies in the future.     

Discovery of 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4: Biological evaluation and docking studies

In this study, novel 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4 (PAK4) were discovered and evaluated for their biological activity against PAK4. Among the derivatives studied, promising compounds A2 , B6 , and B8 displayed the highest inhibitory activities against PAK4 (IC₅₀ = 18.4, 5.9, and 20.4 nM, respectively). From the cellular assay, compound B6 exhibited the highest potency with an IC₅₀ value of 2.533 μM against A549 cells. Some compounds were selected for computational ADME (absorption, distribution, metabolism, and elimination) properties and molecular docking studies against PAK4. The detailed structure–activity relationship based on the biochemical activities and molecular docking studies were explored. According to the docking studies, compound B6 had the lowest docking score (docking energy: −7.593 kcal/mol). The molecular docking simulation indicated the binding mode between compound B6 and PAK4. All these results suggest compound B6 as a useful candidate for the development of a PAK4 inhibitor.     

Synthesis,anticancer activity,and molecular modeling of etodolac‐thioether derivatives as potent methionine aminopeptidase (type II) inhibitors

A series of (R,S)‐1‐{[5‐(substituted)sulfanyl‐4‐substituted‐4H‐1,2,4‐triazole‐3‐yl]methyl}‐1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indoles ( 5a–v ) were designed and synthesized using a five‐step synthetic protocol that involves substituted benzyl chlorides and (R,S)‐5‐[(1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐yl)methyl]‐4‐substituted‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) colorimetric method against VERO, HEPG2 (human hepatocellular liver carcinoma), SKOV3 (ovarian carcinoma), MCF7 (human breast adenocarcinoma), PC3 and DU145 (prostate carcinoma) cells at 10^?5 M (10 μM) for 24 h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC₅₀ = 7.22 and 5.10 μM, respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k , 5s , and 5v showed the most potent biological activity against the PC3 cancer cell line (IC₅₀ = 8.18, 3.10, and 4.00 μM, respectively) and did not display cytotoxicity. Moreover, these compounds were evaluated for caspase‐3, ‐9, and ‐8 protein expression and activation in the apoptosis pathway for 6, 12, and 24 h, which play a key role in the treatment of cancer. In this study, we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.

     

Combined comparative molecular field analysis,comparative molecular similarity indices analysis,molecular docking and molecular dynamics studies of histone deacetylase 6 inhibitors

Human histone deacetylase isoform 6 (HDAC6) has been shown to have an immense role in cell motility and aggresome formation and is being an attractive selective target for the treatment of multiple tumour types and neurodegenerative conditions. The discovery of selective HDAC6 inhibitors with new chemical functionalities is therefore of utmost interest to researchers. In order to examine the structural requirements for HDAC6‐specific inhibitors and to derive predictive model which can be used for designing new selective HDAC6 inhibitors, a three‐dimensional quantitative structure–activity relationship study was carried out on a diverse set of ligands using common feature‐based pharmacophore alignment followed by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The models displayed high correlation of 0.978 and 0.991 for best CoMFA and CoMSIA models, respectively, and a good statistical significance. The model could be used for predicting activities of the test set compounds as well as for deriving useful information regarding steric, electrostatic, hydrophobic properties of the molecules used in this study. Further, the training and test set molecules were docked into the HDAC6 binding site and molecular dynamics was carried out to suggest structural requirements for design of new inhibitors.     

Design,synthesis, and molecular docking study of new monastrol analogues as kinesin spindle protein inhibitors

Lung, colorectal, and breast cancers are the top three types of cancer by incidence and are responsible for one-third of the cancer incidence and mortality. A series of 18 3,4-dihydropyrimidine analogues bearing a 1,2-methylenedioxybenzene component at position 4 with diverse side chains at positions 5 and 6 was designed and synthesized as inhibitors of the Eg5 kinesin enzyme. Target compounds were screened for their anticancer activity according to the NCI-USA protocol toward a panel of 60 cancer cell lines. Compounds 12a and 12b displayed the best antiproliferation activity against many cell lines. Interestingly, compound 12a displayed lethal effects against non-small-cell lung cancer NCI-H522 cells (−42.26%) and MDA-MB-468 breast cancer cells (−1.10%) at a single-dose assay concentration of 10⁻⁵ M. Compounds 11c, 11d, 11g, 12a – d, 13, 15 , and 18a were assayed against the kinesin enzyme, with IC₅₀ values ranging from 1.2 to 18.71 μM, which were more potent compared with monastrol (IC₅₀ = 20 μM). Cell cycle analysis of NCI-H522 cells treated with compound 12a showed cell cycle arrest at the G2/M phase. Furthermore, the expression levels of active caspase-3 and -9 were measured. A molecular docking study was performed for some demonstrative compounds as well as monastrol docked into the allosteric binding site of the kinesin spindle protein.     

Design,synthesis, and cytotoxicity screening of new synthesized imidazolidine-2-thiones as VEGFR-2 enzyme inhibitors

A series of imidazolin-2-thione derivatives was synthesized and structurally confirmed through the use of different spectroscopic techniques such as infrared, nuclear magnetic resonance, and mass spectrometry along with elemental analyses. The breast cancer cell line MCF-7 was utilized in the evaluation of the cytotoxic activity of the prepared molecules. The tested molecules 3 and 7 exhibited the best results on MCF-7 cells, with mean IC₅₀ values of 3.26 and 4.31 µM, respectively. The results of the VEGFR-2 assay indicated that compounds 3 and 7 displayed a good inhibition of the VEGFR-2 kinase enzyme. Additionally, DNA flow cytometry of compounds 3 and 7 showed cell cycle arrest at the G0/G1 phase, cell apoptosis, and marked DNA fragmentation in MCF-7 cells. Finally, compounds 3 and 7 were proved to upregulate the activation of effector caspase-3/7, as presented by the caspase-3/7 green flow cytometry assay.     

Synthesis and docking studies of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamide analogues as potential alkaline phosphatase inhibitors

A series of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a–i were synthesized as alkaline phosphatase inhibitors. The intermediate 5-substituted 1,3,4-oxadiazole-2-thione 4 was synthesized starting with hippuric acid. Hippuric acid in the first step was converted into corresponding methyl ester 2 which upon reaction with hydrazine hydrate furnished the formation of hydrazide 3 . The hippuric acid hydrazide was then cyclized into 5-substituted 1,3,4-oxadiazole-2-thione 4 . The intermediate 4 was then reacted with alkyl or aryl halides 5a–5i to afford the title compounds N-(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a–i . The bioassay results showed that compounds 6a–i exhibited good to excellent alkaline phosphatase inhibitory activity. The most potent activity was exhibited by the compound 6i having IC₅₀ value 0.420 μM, whereas IC₅₀ value of standard (KH₂PO₄) was 2.80 μM. Molecular docking studies was performed against alkaline phosphatase enzyme (PDBID 1EW2) to check binding affinity of the synthesized compounds 6a–i against target protein. The docking results showed that three compounds 6c , 6e , and 6i have maximum binding interactions with binding energy values of −8 kcal/mol. The compound 6i displayed the interactions of oxadiazole ring nitrogen with amino acid His265 having a binding distance 2.13 Ǻ. It was concluded from our results that synthesized compounds, especially compound 6i may serve as lead structure to design more potent inhibitors of human alkaline phosphatase.     

Identification of novel topoisomerase II alpha inhibitors by virtual screening,molecular docking,and bioassay

Breast cancer is one of the most common tumors, and its treatment still leaves room for improvement. Topoisomerase II alpha is a potential target for the treatment of human diseases such as breast cancer. In this article, we attempted to discover a novel anticancer drug. We have used the topoisomerase II alpha protein-Homo sapiens (Human) to hierarchically screen the Maybridge database. Based on their docking score, the top hit compounds have been assayed for inhibition in a topoisomerase II pBR322 DNA relaxation assay in vitro. Candidate compound 6 (CP6) was found to have the best inhibitory effect for topoisomerase II among the 20 tested compounds. In addition, CP6 had potent cytotoxicity against eight tested tumor cell lines. At the same time, CP6 was shown to have potential anti-multidrug resistance capabilities. This study identifies CP6, which can contribute to the development of new topoisomerase II inhibitors as anticancer agents.     

Design,synthesis, biological evaluation,and molecular docking of novel flavones as H3R inhibitors

A series of novel flavone derivatives were designed, synthesized, and evaluated for their H₃R inhibitory activity. The results showed that four compounds exhibited significant anti‐H₃R activity. Molecular docking experiments indicated that a salt bridge, hydrogen‐bonding, and hydrophobic interactions all contributed to interactions between inhibitors and H₃R.     

(Z)-5-(4-Methoxybenzylidene)thiazolidine-2,4-dione, a novel readily available and orally active glitazone, attenuates the bleomycin-induced pulmonary fibrosis in vivo

Idiopathic pulmonary fibrosis is regarded as a lethal chronic disease accompanied with excessive collagen disposition. In the early stage, monocyte chemotactic protein-1 (MCP-1) plays a crucial role in the process. Our previously screening with a vitro assay through inhibition of chemotaxis of RAW264.7 cells stimulated by MCP-1 proved that several analogues of thiazolidinediones, especially (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (SKLB010), had potency of protecting acute liver injury in vivo without obvious toxicity. The present study aimed to investigate the preventive effect of SKLB010 in bleomycin-induced pulmonary fibrosis and further explore the underlying mechanisms. Bleomycin (BLM) was injected intratracheally at a single dose of 5 U kg(-1) for pulmonary fibrosis induction. SKLB010 (25, 50 mg/kg/d) was respectively administrated by gavages 1 d prior to BLM administration and continued to the end of the study (for 4 weeks). Our results demonstrated that SKLB010 diminished the increase of macrophage, neutrophil and lymphocyte counts as well as the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in bronchoalveolar lavage fluid on day 14 (p<0.05). Moreover, oral gavages of SKLB010 also ameliorated histological changes and significantly suppressed collagen deposition on day 28. The treatment with SKLB010 exerted approximately 34.6% the hydroxyproline content reduction for 25 mg/kg dose and 56.7% reduction for 50 mg/kg dose in contrast to bleomycin-induced group (p<0.05). Meanwhile, SKLB010 inhibited the overexpression of tumor growth factor (TGF)-β1 and Smad3 in a dose-dependent manner. In conclusion, our results showed that SKLB010 could attenuate the BLM-induced pulmonary fibrosis in vivo and therefore be a promising anti-fibrogenic candidate.