Synthesis,Biological Evaluation and Molecular Docking of Novel Phenylpyrimidine Derivatives as Potential Anticancer Agents

Based on our previous researches, a novel phenylpyrimidine pharmacophore model was proposed and fifteen derivatives were synthesized and characterized by means of spectroscopy methods. The inhibitory effects of them were screened against HeLa cell line by virtue of MTT assay in vitro. The results indicate some of the phenylpyrimidine derivatives exhibit potent biological activities. Among them, compounds 6g and 6h exhibit the best activity at half maximal inhibitory concentrations of 1.5 and 2.8 μmol/L, respectively. These compounds also exhibit good activities against HepG2 cell line and MCF-7 cell line. FLT-3 kinase was screened as the most potent molecular target. Computational docking between compound 6g and FLT-3 was carried out to interpret the binding mode. The results show phenylpyrimidine derivatives have effective antitumor activities, which provides a base for further research of them as antitumor agents.     

Design,Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.     

Novel Pyridothienopyrimidine Derivatives: Design,Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents

The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC₅₀ ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC₅₀ ranges of 7.27–17.29 nM, higher than that of erlotinib, IC₅₀ = 27.01 nM.     

Synthesis,Structure and Biological Evaluation of Thiourea Derivatives as Antitumor Agents

Two substituted-3-phenylthiourea derivatives have been synthesized and characteri- zed by elemental analysis, 1H NMR, MS and single-crystal X-ray diffraction. Structural stabili- zation of them followed by intramolecular as well as intermolecular H-bonds makes these molecules as perfect examples in molecular recognition with self-complementary donor and acceptor units within a single molecule. The antitumor activities of compounds I and 2 against breast adeno carcinoma cell line MCF-7 have been evaluated by MTT method. Docking simulations have also been performed to position compounds into the telomerase active sites so as to determine their probable binding models.     

Synthesis,Docking and Biological Evaluation of Isoquinolonic Acid Derivatives

A series of isoquinolonic acid derivatives（4a-4o） was synthesized via one-pot synthesis for their anti-tumor activity. The structures of all the targeted compounds were confirmed by IH nuclear magnetic resonance （IH NMR） spectrometry and mass spectrometry（MS）. The anti-tumor activities of compounds 4a-4o against MG63（human osteosarcoma cells） and B16-F10（mouse melanoma cells） were examined. To evaluate the antitumor effect of the as-synthesized compounds, we compared the half maximal inhibitory concentration（1C50） of compounds 4a--4o to that of camptothecin（CPT） which appeared to be active against a broad range of human cancers. Among all the compounds, compound 41 shows the most potent biological activity against MG63 cells[IC50=（2.16i0.26） μmol/L] and B16-F10 cells[IC50=（6.95±0.24）μmol/L], thus providing useful information for the antitumor activity and potential practical use of isoquinolonic acid compounds. In addition, we screened out an efficient compound（41） that shows potential inhibit activity against Topoisomerase 1（Topo 1） by docking simulation.     

Design,Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C₁ and C₄ on the A ring of sinomenine. Twenty-three compounds were synthesized and characterized by spectroscopy (IR, ¹H-NMR, ¹³C-NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer-related core targets and verified their interaction with derivatives through molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives might be a promising lead for the development of new anticancer agents.     

Design,Synthesis, and Thrombin Inhibitory Activity Evaluation of Some Novel Benzimidazole Derivatives

Some benzimidazole derivatives were designed and screened via molecular docking. Six compounds which obtained high scores were selected for synthesis and all compounds were characterized by ¹H‐ and ¹³C‐NMR, and HR‐ESI‐MS. Subsequently, these compounds were evaluated for their inhibitory activities on thrombin. Compound 5a (IC₅₀ 3.11 nm ) showed a better activity than the reference argatroban (IC₅₀ 9.88 nm ). These results, along with related molecular model studies, indicated that 5a could be a potential thrombin inhibitor for further research.     

Design,Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives Bearing Semicarbazone Moiety as Antitumor Agents

A series of novel benzothiazole derivatives bearing semicarbazone as a linker was designed and synthesized, and their in vitro antitumor activities were evaluated against four cancer cell lines(HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 12a―12i with fluoro-substituted benzyl-1H-indole moiety displayed more potent activity than those with phenyl moiety. The most promising compound 12d exhibited excellent antitumor activity with IC₅₀ values of 0.015, 0.28, 1.53 and 0.68 μmol/L against the four tested cell lines respectively.     

欧芹酚甲醚腙类衍生物的合成及抗乙酰胆碱酯酶活性研究

以香豆素类化合物欧芹酚甲醚为先导化合物,设计合成了15个欧芹酚甲醚腙类衍生物,所有目标化合物经熔点、¹H NMR和MS进行结构确证。体外抑制乙酰胆碱酯酶活性结果表明,在100μmol/L浓度下,目标化合物3d对乙酰胆碱酯酶具有较强的抑制活性,其抑制率达到66.1%。初步构效关系表明,在欧芹酚甲醚腙类化合物的苯环上引入斥电子基能提高对乙酰胆碱酯酶的抑制活性。分子对接表明化合物3d可以和乙酰胆碱酯酶的催化活性中心部位显著结合。     

Efficient One-pot Synthesis of Pyrrolo[2,1-a]isoquinoline and Pyrrolo[1,2-a]quinoline Derivatives

A one-pot sequential reaction for efficient synthesis of pyrrolo[2,1-a]isoquinoline and pyrrolo[1,2-a]-quinoline derivatives has been developed. The reaction included firstly the Cu-catalyzed three-component reaction of isoquinoline(quinoline), acetylenedicarboxylate and alkynylbenzene and then Cs₂CO₃-promoted intramolecular cyclization reaction of initially formed 1-alkenyl-2-alkynyl-1,2-dihydroisoquinoline(1,2-dihydroquinoline).     

Synthesis,Characterization, and Biological Evaluation of Some Novel Pyrazolo[5,1-b]thiazole Derivatives as Potential Antimicrobial and Anticancer Agents

The pharmacological activities of thiazole and pyrazole moieties as antimicrobial and anticancer agents have been thoroughly described in many literature reviews. In this study, a convenient synthesis of novel pyrazolo[5,1-b]thiazole-based heterocycles was carried out. The synthesized compounds were characterized by IR, ¹H and ¹³C NMR spectroscopy and mass spectrometry. Some selected examples were screened and evaluated for their antimicrobial and anticancer activities and showed promising results. These products could serve as leading compounds in the future design of new drug molecules.     

Design,Synthesis and Biological Activity of Novel Chalcone Derivatives as Anti-influenza Agents

A series of novel chalcone derivatives was designed and synthesized via a suitable synthetic strategy in good yields using commercially available 2-amino-4-nitrophenol as an initiator. The structures of the target compounds were confirmed by means of ¹H NMR, ¹³C NMR and high-resolution mass spectrometry(HRMS). And the ability of the target compounds to inhibit influenza viruses was evaluated. These compounds showed moderate inhibitory activity against influenza A(H9N2 and H5N1) viruses. Within this series, compounds S14 and S15 with good potency(IC₅₀=40.3-51.5μmol/L) could be used as lead compounds in the future.     

Synthesis and Biological Evaluation of Novel Tricyclic Oximino Derivatives as Antitumor Agents

A series of novel alkylthio/sulfinyl-8H-thieno[2,3-b]pyrrolizin-8-oximino derivatives Ⅴ1--Ⅷ15 were designed and synthesized as antitumor agents. Their structures were confirmed using IR, ^1H NMR, elemental analysis, and MS. The antitumor activities of all the target compounds were tested by the MTT method in vitro against Bel-7402, HT-1080, SGC-7901, and A549 Cell Lines. Among them, compound Ⅵ9 displayed a promising antitumor activity superior to that of Cisplatin.     

Design,Synthesis and Pharmacological Evaluation of Novel 4-Phenoxyquinoline Derivatives as Potential Antitumor Agents

A series of novel 4-phenoxyquinoline derivatives containing 3-amino-2-cyano-acrylamide framework was designed and synthesized, and the in vitro cytotoxic activities of them against five cancer cell lines(HT-29, H460, A549, MKN-45, and U87MG) were evaluated. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines as compared with Foretinib. The studies of their preliminary structure-activity relationships(SARs) indicate that the compounds containing methyl groups, especially methyl groups at 4-position of the phenyl ring(moiety B) are more effective. Among them, compound 36 shows the most potent antitumor activities with IC₅₀ values of 0.04, 0.09, 0.67, 0.39 and 1.10 μmol/L against HT-29, H460, A549, MKN-45 and U87MG cell lines, respectively.     

Design,Synthesis and Biological Evaluation of Novel Thienylpyridyl- and Thioether-Containing Acetamides and Their Derivatives as Pesticidal Agents

Referring to the structural information of the “hit” compound A from the reported pharmacophore-based virtual screening, a series of novel thienylpyridyl- and thioether/sulfoxide/sulfone-containing acetamide derivatives have been designed and synthesized. The structures of new compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. The single-crystal structure of A was firstly reported. All the new synthesized compounds were evaluated for insecticidal activities on Mythimna separata Walker and Plutella xylostella L. Through a step-by-step structural optimization, the high insecticidal agents, especially towards Plutella xylostella L., have been found, and thienylpyridyl- and sulfone/thioether-containing acetamides Iq, Io, Ib and A, which are comparable with the control insecticides cartap, triflumuron and chlorantraniliprole in the present study, can be used as novel lead structures for new insecticides innovation research. In addition, some of the compounds, e.g., A, Ih, Id, Io and Iq, also exhibited favourable fungicidal activities against Physalospora piricola, Rhizoctonia cerealis and Sclerotinia sclerotiorum and would provide useful guidance for the design and development of new fungicides.     

Design,Synthesis and Biological Evaluation of Lophanic Acid Derivatives as Antifungal and Antibacterial Agents

In order to discover more promising antifungal and antibacterial agents, a series of new derivatives were designed and synthesized by structure modification based on the naturally occurring antimicrobial compound lophanic acid. The structures of all the target compounds were well characterized by spectroscopic data. The stereochemistry of these compounds was further determined through the X-ray diffraction analysis of 6a. The synthetic compounds were evaluated for their antimicrobial activities against filamentous fungi (T. rubrum, T. mentagrophytes), yeasts (C. neoformans, C. albicans) and Gram-positive and Gram-negative bacteria (MRSA, S. mutans, S. sobrinus, and E. coli). Among them, 3d and 3i are found as the most promising leads that showed potent inhibitory effects against all the tested fungal and bacterial strains except for E. coli. The presence of the C-20 carboxylic ester groups and the free hydroxy group at C-13 was found to be essential for the antifungal and antibacterial activities of the lophanic acid derivatives.     

Synthesis,ABTS-Radical Scavenging Activity,and Antiproliferative and Molecular Docking Studies of Novel Pyrrolo[1,2-a]quinoline Derivatives

A new 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)-radical scavenging and antiproliferative agents of pyrrolo[1,2-a]quinoline derivatives have been synthesized. An efficient method for the synthesis of 14 novel diversified pyrrolo[1,2-a]quinoline derivatives has been described using 4-(1,3-dioxolan-2-yl)quinoline and different phenacyl bromides in acetone and followed by reacting with different acetylenes in dimethylformamide/K₂CO₃. The structure of the newly synthesized compounds was determined by infrared, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. The in vitro antioxidant activity revealed that among all the tested compounds 5n exhibited maximum scavenging activity with ABTS. Compound 5b has showed good antiproliferative activity as an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase.     

Novel Coumarin 7-Carboxamide/Sulfonamide Derivatives as Potential Fungicidal Agents: Design,Synthesis, and Biological Evaluation

Coumarin compounds have a variety of biological activities such as anti-tumor, anti-coagulation, anti-HIV, anti-fungal, and insecticidal. Amide and sulfonamide compounds have been used as fungicides for half a century, and dozens of varieties have been developed so far. This study focused on the introduction of carboxamide and sulfonamide moieties in a coumarin core to discover novel derivatives. Based on this strategy, we synthesized two series of novel carboxamide and sulfonamide substituted coumarin derivatives, and their fungicidal activity was also investigated. Some designed compounds possessed potential activities against six phytopathogenic fungi in the primary assays, highlighted by compound 6r. Compound 6r exhibited stronger fungicidal activity against Botrytis cinerea (EC₅₀ = 20.52 µg/mL) and will be the lead structure for further study.