Synthesis of febrifuginol analogues and evaluation of their biological activities

A new series of febrifuginol analogues was prepared from l-glutamic acid. An antimalarial activity evaluation against chloroquine-sensitive (T96) and chloroquine-resistant (K1) Plasmodium falciparum indicated that all the tested compounds had very strong inhibitory activity. Compounds 4 and 17b′ were inactive against KB, MCF7, HepG2 and LU1 cell lines even at a concentration of 100 μM, while they exhibited significant inhibition towards P. falciparum. Comparison of the antimalarial activity and the cytotoxic properties revealed that the 2′S isomers were more active than the corresponding 2′R isomers for this series of febrifuginol analogues, indicating that the C-2′ position is critical for the biological activity of this class of compounds.     

Design and synthesis of some novel pyridothienopyrimidine derivatives and their biological evaluation as antimicrobial and anticancer agents targeting EGFR enzyme

A new series of pyridothienopyrimidine derivatives was designed and evaluated as antimicrobial and anticancer agents. The target compounds were synthesized starting with 3-aminothieno[2,3-b]pyridine-2-carboxamide derivative 1 which underwent cyclocondensation reaction with aromatic aldehydes to give the key intermediates 2a,b. By further treatment of 2a,b with various reagents, the target 2,4-disubstituted-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidines 3a,b–11a,b were obtained. To evaluate the antimicrobial activity of the new compounds, they were tested against five bacterial and five fungal strains. Compounds 6c, 8b, 9a and 9b revealed the most significant antimicrobial activity against the tested microorganisms with MIC values range (4–16 μg/mL). Also, compounds 2a,b–11a,b were screened for their in vitro cytotoxic activity against HepG-2 and MCF-7 cancer cell lines compared with doxorubicin and cisplatin as references drugs. Moreover, compounds (2b, 4a, 6a, 7b, 7c and 9a) which exhibited the most potent anticancer activity, were further subjected to EGFR^WT enzyme inhibition assay utilizing erlotinib as a standard drug. The compounds 6a, 7b, 7c and 9a which showed the most promising suppression effects were also evaluated as inhibitors against the mutant forms EGFR^L858R and EGFR^T790M. The 4-aminopyrazolone analogue 9a showed superior anticancer activity against both HepG-2 and MCF-7 cell lines (IC50 = 1.27, 10.80 μM, respectively) and more potent enzymatic inhibition activity against EGFR^WT and its mutant forms EGFR^L858R and EGFR^T790M than that obtained by erlotinib (IC₅₀ = 0.021, 0.053, 0.081 µM, respectively, IC_50erlotinib; 0.027, 0.069, 0.550 µM, respectively). Finally, the molecular docking study showed good binding patterns of the most active compounds with the prospective target EGFR^WT.     

Synthesis,evaluation and docking studies of some 4-thiazolone derivatives as effective lipoxygenase inhibitors

Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model, whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38, and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC₅₀?=?12.98 µM and IC₅₀?=?12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC₅₀?>?50 µM and, COX-2; IC₅₀?>?50 µM). The enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are promising pharmacophore for anti-inflammatory activity.     

Design,synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects

A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI₅₀ values ranging from 0.70 µM to 1.20 µM, compared to doxorubicin GI₅₀ value = 1.10 µM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC₅₀ values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC₅₀ = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC₅₀ values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC₅₀ = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking score.     

4-Ferrocenylpyridine- and 4-Ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5-dicarbonitriles: Multi-Component Synthesis, Structures and Electrochemistry

The reactions of 2-cyano-3-ferrocenylacrylonitrile (1) with malononitrile (2) in a MeOH/H₂O or 2-PrOH/H₂O medium in the presence of Na₂CO₃ afforded 6-alkoxy-2-amino-4-ferrocenylpyridine-3,5-dicarbonitriles 3a,b (multi-component condensation) and 6-alkoxy-2-amino-4-ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5-dicarbonitriles 4a,b (multi-component cyclodimerization). Analogous reactions of 1 with 2 in an MeOH/H₂O medium in the presence of NaOH, piperidine, or morpholine gave compounds 3a, 4a and 2-amino-4-ferrocenyl-6-hydroxy-, 6-piperidino- and 6-morpholinopyridine-3,5-dicarbonitriles 3c-e, respectively. The structures of the compounds 3b, 4a and 4b were established by the spectroscopic data and X-ray diffraction analysis. The electrochemical behaviour of compounds 3b, 3d and 4b was investigated by means of cyclic voltammetry.     

Anticancer and antimicrobial evaluation of newly synthesized steroidal 5,6 fused benzothiazines

A series of new 5α-cholestano [5,6-b] benzothiazines (4–6) has been synthesized by the reaction of 5α-cholestan-6-one (1–3) with 2-aminothiophenol in the presence of iodine. The structures of newly synthesized compounds have been established on the basis of spectral and analytical data. Compounds (1–6) were screened for in vitro anticancer activity against the human cancer cell lines; SW480 (colon adenocarcinoma cells), A549 (lung carcinoma cells), HepG2 (hepatic carcinoma cells) and HeLa (cervical cancer cells) using MTT assay during which the products (4–6) showed marked increase in anticancer activity and in particular, compound 6 showed IC₅₀ = 13.73 μmol L⁻¹ against HeLa cells, being more effective than Doxorubicin against the same cells. Compounds 4 and 6 also showed minimum IC₅₀ of 15.83 μmol L⁻¹ and 16.89 μmol L⁻¹ against HepG2 and A549 cells, respectively. Compounds (1–6) were also tested for in vitro antimicrobial activity against different bacterial as well as fungal strains during which newly synthesized compounds (4–6) were found more potent than starting compounds (1–3). Compound 4 was found to be more potent than the reference drug, Chloramphenicol, in the case of Escherichia coli while compound 5 was found almost equally potential antifungal agent against P. marneffei in comparison with the reference drug, Nystatin.     

Synthesis and cytotoxicity screening of derivatives of the simplified ecteinascidin pentacyclic skeleton as anticancer agents

A series of new ecteinascidin pentacyclic-derived compounds bearing aryl carboxylic amide side chains at C-22 have been designed and synthesized. The cytotoxicity evaluation confirmed their potent antitumor activity by use of eight different cell lines. Studies on the structure-activity relationship of them showed that the chemical structure of C-22 pendants have great effects on the tumor-killing activity. Notably, Compounds 6, 7 and 8 with benzo[b]thiophene-2-carboxamide pendants exhibited excellent broad-spectrum antitumor activity with the low IC₅₀ values of 10^?7?M.     

Synthesis and pharmacological evaluation of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles: A condensed bridgehead nitrogen heterocyclic system

A series of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a–j and 5a–d) were synthesized by condensation of 4-amino-5-diphenylmethyl-4H-1,2,4-triazole-3-thiol with various substituted aromatic acids and aryl/alkyl-isothiocyanates. The structures of synthesized compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectroscopic studies. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic, lipid peroxidation and hepatotoxic effects. Compounds 6-(4-chlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (4a) and 6-(2,4-dichlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole(4c) emerged as the most active compounds of the series and were moderately more potent than the standard drug ibuprofen.     

Multistep synthesis and screening of heterocyclic tetrads containing furan,pyrazoline, thiazole and triazole (or oxadiazole) as antimicrobial and anticancer agents

In the present study novel heterocyclic tetrads containing furan, pyrazoline, thiazole and triazole (or oxadiazole) (1, 2, 3, 4a-e and 5a-e) were designed and synthesized and investigated for their antimicrobial (against selected bacteria and fungi) and anticancer potential. The molecules 4e and 5e containing 4-fluoro phenyl and 4-fluoro benzyl substituents showed promising antimicrobial (antibacterial and antifungal activities with MICs ranging between 0.5 and 8 µg/mL. Compounds 3 exhibited potent anticancer activity with an IC₅₀ value of 0.49 ± 1.45 µM against the human gastric cancer cell line (BGC-823) whereas compound 4e displayed an IC₅₀ value of 0.65 ± 0.53 µM against breast cancer (MCF-7) cell line respectively. All compounds showed selective toxicity against the cancer cell lines compared to human normal liver cell lines. Molecular docking studies of the most potent compounds (3 and 4e) against selected microbial and cancer proteins revealed the crucial binding interactions of the potent compounds with the target enzymes. Compounds 3 and 4e are promising lead molecules to be developed as potential drug candidates.     

胍基木吡喃糖苷的合成及其抗HIV蛋白酶活性

2,3,4-三-O-乙酰基-b-D-木吡喃糖基异硫氰酸酯1与2-氨基-4/6-取代-苯并噻唑2a～2e反应, 生成糖基硫脲衍生物3a～3e, 再在伯胺存在下经氯化汞脱硫, 得到一系列新的胍基木吡喃糖苷类化合物4a～4e, 5a～5e, 6a～6e, 7a～7e, 所有新化合物的结构均经IR, ¹H NMR, MS谱和元素分析证实, 所得产物均为β-构型. 生物活性测试结果表明, 化合物4c, 5b, 6b～6d, 7b等对HIV-1蛋白酶表现出了较高的抑制活性.     

Novel indan-1,3-dione derivatives: Design,green synthesis,effect against tomato damping-off disease caused by Fusarium oxysporum and in silico molecular docking study

An effective method for synthesizing series of twenty-two new compounds 1, 2a,b, 3, 4a,b, 5a-e, 7, 8, 9, 10, 12, 13a-d, 15a,b was performed starting from reaction of 1,2,3-indenetrione thiourea, and ethyl cyanoacetate under microwave irradiation and / or 2-(1,3-dioxo-1H-inden-2(3H)-ylidene) hydrazine carbothioamide with acetic anhydride. Chemical structure of the obtained products has been established by spectroscopic techniques including FTIR, ¹H NMR, ¹³C NMR, DEPT-135, and mass spectroscopy. The designed new compounds have been successfully examined in-vitro for their antifungal activities. The relation between the structure of the synthesized compounds and their activity against tomato damping-off disease caused by Fusarium oxysporum fungi was studied and favourable results were obtained. The antifungal studies indicated that compounds 1, 7, 4a and 5a-d exerted the highest antifungal activities, while 3 and 4b recorded the lowest effect. The obtained results confirmed the possibility of the application of ethyl 6′-amino-1,3-dioxo-2′-thioxo-1,2′,3,3′-tetrahydro-1′H-spiro[indene-2,4′-pyrimidine]-5′-carboxylate 1 as a new effective regulator of the vegetative growth of tomatoes. The molecular docking analysis was performed within succinate dehydrogenase (SDH) as a target enzyme in order to rationalize the promising findings obtained for the active compounds 1, 2a,b, 5a-d, 7, 8, 9, 10, 12, and 13a.     

Synthesis,characterization and biological evaluation of purine nucleoside analogues

We present a convenient route for the synthesis of C6-amino-C5′-N-cyclopropyl carboxamido-C2-alkynylated purine nucleoside analogues 11a–g via Sonogashira coupling reaction. The nine step synthesis is easy to perform, employing commercially available reagents. Compound 9 is used as key intermediate for the synthesis of analogues 11a–g. Synthetic intermediates and final products are appropriately characterized by IR, ¹H NMR, ¹³C NMR and Mass. The modified nucleoside analogues 11a–g is evaluated for in vitro anticancer activity against MDA-MB-231 and Caco-2 cell lines. Screening data reveals that compounds 11b and 11e displayed potent IC₅₀ value of 7.9, 6.8 µg/mL respectively against MDA-MB-231 and of 7.5, 8.3 µg/mL respectively against Caco-2 than the standard drug doxorubicin, thus establishing the potential anti-cancer properties of these newer derivatives.     

Novel coumarin derivatives containing 1,2,4-triazole, 4,5-dicyanoimidazole and purine moieties: synthesis and evaluation of their cytostatic activity

We report here on the synthesis and in vitro anti-tumor effects of a series of novel 1,2,4-triazole (compounds 3-6), 4,5-dicyanoimidazole (compound 7), and purine (compounds 8-13) coumarin derivatives and their acyclic nucleoside analogues 14-18. Structures of novel compounds 3-18 were deduced from their ¹H- and ¹³C-NMR and corresponding mass spectra. Results of anti-proliferative assays performed on a panel of selected human tumor cell lines revealed that compound 6 had moderate cytostatic activity against the HeLa cell line (IC₅₀ = 35 μM), whereas compound 10 showed moderate activity against the HeLa (IC₅₀ = 33 μM), HepG2 (IC₅₀ = 25 μM) and SW620 (IC₅₀ = 35 μM) cell lines. These compounds showed no cytotoxic effects on normal (diploid) human fibroblasts.     

Synthesis of bengamide E analogues and their cytotoxic activity

A series of bengamide E analogues were prepared from the corresponding polyketide chain and amino acids via amide coupling reactions. Opening of the polyketide chain lactone ring with α-aminolactams was successfully achieved under microwave irradiation in the presence of sodium 2-ethyl hexanoate. A cytotoxic activity evaluation against a panel of cancer cell lines (KB, HepG-2, Lu-1, MCF-7, HL-60 and Hela) indicated that the 2′R analogues were generally more cytotoxic than the 2′S analogues. Additionally, several analogues exhibited selective inhibition against various cancer cell lines: compounds 32a and 32b selectively inhibited MCF-7 cells, while 33b and 35b were more sensitive toward Lu-1 and HepG-2, respectively. Notably, some of the synthetic analogues possess cytotoxic activities with IC₅₀ values less than 1 µM.     

Arylnaphthalide lignans from Saussurea medusa and their anti-inflammatory activities

Five new arylnaphthalide lignans (1 ? 4a/4b), together with five known analogues (5–9), were isolated from whole plants of Saussurea medusa. Compound 4 was characterized as an aryltetralin lignan with an unusual C-7′-C-9 oxygen bridge group, and a chiral HPLC analysis was carried out to afford one pair of enantiomers (4a/4b). Structures of the new compounds were elucidated by extensive spectroscopic and electronic circular dichroism (ECD) calculations. All compounds were firstly isolated from S. medusa, and compounds 1–5, 7 and 8 had never been obtained from the genus Saussurea previously. Furthermore, this is the first report of arylnaphthalide lignans isolated from S. medusa. anti-inflammatory activities of the compounds were evaluated by determining their inhibitory activities on the production of NO by LPS-stimulated RAW 264.7 cells. Compounds (?)-4a and 5 exerted the significant inhibition activities with IC₅₀ values of 13.4 ± 1.5 and 15.7 ± 1.1 μM, respectively, which even exceeded the positive control quercetin (IC₅₀ = 15.9 ± 1.2 μM). Compounds 2, (+)-4b, 6 and 9 exhibited moderate inhibitory activities with IC₅₀ values ranging from 19.7 ± 1.9 to 47.4 ± 3.1 μM. Further analysis by molecular docking showed that almost all the active compounds could interact with the amino acid residues of iNOS proteins, which also supported their anti-inflammatory activities.     

Synthesis,characterization and in vitro antimicrobial screening of quinoline nucleus containing 1,3,4-oxadiazole and 2-azetidinone derivatives

A series of 3-chloro-1-(aryl)-4-(2-(2-chloro-6-methylquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-4-ethyl-azetidin-2-ones (V)_1–12 have been synthesized and characterized by IR, ¹H NMR, ¹³C NMR and mass spectra. Synthesized compounds were screened for their antibacterial activity against four different strains like Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pyogenes, while antifungal activity was determined against three different strains like Candida albicans, Aspergillus niger and Aspergillus clavatus. On the basis of statistical analysis, it has been observed that compounds gave significant co-relation.     

Novel aromatic carboxamides from dehydroabietylamine as potential fungicides: Design,synthesis and antifungal evaluation

The present study was carried out to design and synthesize a number of novel aromatic carboxamide derivatives of dehydroabietylamine. The preliminary antifungal assay indicated that most of title compounds displayed moderate to good antifungal activity toward the six fungal strains in vitro. Compounds 3i, 3q, 4b and 4d showed significant antifungal activity against Sclerotinia sclerotiorum, with EC₅₀ values ranging from 0.067 ～ 0.393 mg/L. Compounds 3i, 4b and 4d also showed pronounced mycelial growth inhibition activities against B. cinerea and A. solani. Furthermore, in the in vivo assay, compound 4b exhibited brilliant protective activity against S. sclerotiorum-infected rape leaves. Meanwhile, the in vivo bioassay on tomato plants infected by B. cinerea showed that compound 3i and 4d displayed excellent protective activity at 200 mg/L, which were near to boscalid. Primary mechanistic study revealed that 4b could inhibit sclerotia formation as well as reduce the exopolysaccharide level. SEM and TEM analysis indicated that 4b possessed a strong ability to destroy the surface morphology of mycelia, cell structure and seriously interfere with the growth of the fungal pathogen. In addition, 4b exhibited good inhibitory activity (IC₅₀ = 23.3 ± 1.6 μM) toward succinate dehydrogenase (SDH). Molecular modeling study confirmed the binding modes between compound 4b and SDH. The above antifungal results and fungicidal mechanism study revealed that this class of dehydroabietylamine derivatives could be potential SDH inhibitors and lead compounds for novel fungicides development.     

Design, synthesis and antiproliferative activities of novel 5H-pyridazino[4,5-b]indoles

A novel series of 5H-pyridazino[4,5-b]indoles were designed and synthesized in order to find novel potent anticancer compounds.The structures were confirmed by ~1H NMR and MS.Their antiproliferative activities against two cancer cell lines were tested by the MTT method in vitro.Three of compounds (1e,1g,and 1h) exhibited potent antiproliferative activities,especially compound 1h (with IC_(50) values of 5.2μmol/L and 1.9μmol/L against Bel-7402 and HT-1080,respectively).The preliminary structure-activity relationships of 5H-pyridazino[4,5-b]indole derivatives were discussed.     

Etude des petits cycles—XXXVI. Photo-oxygenation d'alkylidenecyclopropanes. Syntheses specifiques d'alkenylcyclopropanols,de β′-hydroxy α-enones et d'α,α′-dienones

The dye-sensitized photo-oxygenation of alkylidenecyclopropanes 1a–4a at –50°C gives the hydroperoxydes 1b–4b, which were reduced in situ by PPh₃ into 1-alkenylcyclopropanols 1c–4c in high yield. At higher temperatures, 1b–4b rearranged exclusively into β′-hydroxy α-enones 1d–4d if pyridine was added (α,α′-dienones 1e–4e are also formed competitively in absence of pyridine). At 3°C the photosensitised oxygenation of alkylidenecyclopropanes 1a–4a gives ketones 1k–4k, cyclobutanones 1i–4i and β′-hydroxy α-enones 1d–4d. The origin of products is discussed.     

Multicomponent synthesis,cytotoxicity, and computational studies of novel imidazopyridazine-based N-phenylbenzamides

A one-pot multicomponent synthesis and application of new imidazopyridazine based N-phenylbenzamides is described. An atom-economical method involving dimethyl phthalate, substituted anilines, and pyridazine-4,5-diamine provided the desired compounds in 120–150 min with 80–85% yield. The reaction was catalyzed with phosphoric acid, and glycerol was used as a safer, greener solvent. Anticancer evaluation against selected cancer cell lines revealed that compound 4e was the most active from the series and exhibited IC₅₀ values below 9.1 µM. Compounds 4h and 4d also displayed good and comparable IC₅₀ values (10.2–12.1 µM). Molecular docking and molecular dynamic studies showed that compound 4e exhibit good binding affinity and stable complex formation with ABL1-kinase protein, respectively. Additional computational predictions such as ADME and drug-likeness demonstrated the potential of the new benzamides as leads for further development.