One-Pot Regioselective Synthesis of Some Novel Isoxazole-Phenothiazine Hybrids and Their Antibacterial Activity

Russian Journal of General Chemistry - Some novel isoxazole-phenothiazine hybrids have been synthesized regioselectively in high yields via Cu(I) catalyzed one-pot reaction of...     

Synthesis and In Vitro Antibacterial Evaluation of Some Novel Annulated Quinazolinone Derivatives

Russian Journal of General Chemistry - A series of novel substituted quinazoline derivatives are synthesized. Antibacterial tests demonstrate their high activity against Gram-positive and...     

Some Novel Thiopyrimidine Nucleoside Analogs: Synthesis and In Vitro Antimicrobial Evaluation

Some new S-alkyl derivatives of indeno[1′,2′:4,5]thieno[2,3-d]pyrimidine 2–8 were prepared starting with pyrimidine-2(1H)-thione derivative (1). Also, treatment of compound 1 with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide or 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose afforded nucleosides 9 and 12, respectively. Furthermore, deprotection of the latter blocked nucleosides was achieved in methanolic ammonia to afford the desired free S-nucleoside derivatives 10 and 13, respectively. Some prepared products were screened for antimicrobial activity, and some of them showed promising activity.     

Semi-Synthesis and In Vitro Anti-Cancer Evaluation of Magnolol Derivatives

Magnolol (MAG), a biphenolic neolignan, has various biological activities including antitumor effects. In this study, 15 MAG derivatives were semi-synthesized and evaluated for their in vitro anticancer activities. From these derivatives, compound 6a exhibited the best cytotoxic activity against four human cancer cell lines, with IC₅₀ values ranging from 20.43 to 28.27 μM. Wound-healing and transwell assays showed that compound 6a significantly inhibited the migration and invasion of MDA-MB-231 cells. In addition, Western blotting experiments, performed using various concentrations of 6a, demonstrated that it downregulates the expression of HIF-1α, MMP-2, and MMP-9 in a concentration-dependent manner. Overall, these results suggest that substituting a benzyl group having F atoms substituted at the C2 position on MAG is a viable strategy for the structural optimization of MAG derivatives as anticancer agents.     

A One-Pot Three-Component Synthesis and Investigation of the In Vitro Mechanistic Anticancer Activity of Highly Functionalized Spirooxindole-Pyrrolidine Heterocyclic Hybrids

With an aim to develop more effective and affordable anticancer agents possessing a unique mechanism of action, we designed and synthesized derivatives of spirooxindole-pyrrolidine heterocyclic hybrids in good yields through a one-pot three-component (3+2) cycloaddition strategy. The synthesized compounds were characterized thoroughly for the physicochemical properties by making use of FT-IR, NMR spectroscopy, and mass spectrometry. Further, these compounds have been evaluated for the influence of anticancer activity against HepG2 cells up to 200 µg/mL concentration. The highly active molecular scaffold was tested for the in-depth mechanistic studies, and it was found that the major pathway of cell death is apoptosis which occurs through the induction of reactive oxygen species followed by the involvement of caspases.     

Design,Synthesis and Antifungal Evaluation of Novel Pyrylium Salt In Vitro and In Vivo

Nowadays, discovering new skeleton antifungal drugs is the direct way to address clinical fungal infections. Pyrylium salt SM21 was screened from a library containing 50,240 small molecules. Several studies about the antifungal activity and mechanism of SM21 have been reported, but the structure–activity relationship of pyrylium salts was not clear. To explore the chemical space of antifungal pyrylium salt SM21, a series of pyrylium salt derivatives were designed and synthesized. Their antifungal activity and structure-activity relationships (SAR) were investigated. Compared with SM21, most of the synthesized compounds exhibited equivalent or improved antifungal activities against Candida albicans in vitro. The synthesized compounds, such as XY10, XY13, XY14, XY16 and XY17 exhibited comparable antifungal activities against C. albicans with MIC values ranging from 0.47 to 1.0 μM. Fortunately, a compound numbered XY12 showed stronger antifungal activities and lower cytotoxicity was obtained. The MIC of compound XY12 against C. albicans was 0.24 μM, and the cytotoxicity decreased 20-fold as compared to SM21. In addition, XY12 was effective against fluconazole-resistant C. albicans and other pathogenic Candida species. More importantly, XY12 could significantly increase the survival rate of mice with a systemic C. albicans infection, which suggested the good antifungal activities of XY12 in vitro and in vivo. Our results indicated that structural modification of pyrylium salts could lead to the discovery of new antifungal drugs.     

“一锅”三组分合成新型1,5-苯并二氮杂䓬类化合物与抗牛病毒性腹泻病毒(BVDV)活性

以特氨酸、邻苯二胺和芳香醛为原料,乙醇为溶剂,对甲苯磺酸为催化剂,多组分一锅法构建了一系列含有吡咯烷酮的1,5-苯并二氮杂?类化合物.该方法反应条件温和,操作简单,产物收率高.探索了抗牛病毒性腹泻病毒(BVDV)病毒活性,结果显示合成的苯二氮?类衍生物具有显著的抗BVDV活性,EC₅₀值好,且无明显的细胞毒性,为抗BVDV制剂的研究提供了有意义的参考物.     

Synthesis and In Vitro Urease Inhibition of Some Novel Benzimidazole‐based Hydrazones

A novel series of N′‐(substituted benzylidene)‐2‐(5,6‐dichloro‐2‐methyl‐1H‐benzimidazol‐1‐yl)acetohydrazides and N′‐(1‐(substituted phenyl)ethylidene)‐2‐(5,6‐dichloro‐2‐methyl‐1H‐benzimidazol‐1‐yl)acetohydrazides were synthesized and then studied for their urease inhibitory activities using thiourea as a standard drug. All newly synthesized compounds were found to exhibit potent inhibitory properties against urease enzyme in the range of IC₅₀ = 0.0155 ± 0.0039–0.0602 ± 0.0071 μM, when compared with the thiourea as standard (IC₅₀ = 0.5115 ± 0.0233 μM). All target molecules were characterized by ¹H‐NMR, ¹³C‐NMR, IR, and electrospray ionization mass spectrometry.     

Synthesis and QSAR Study of Some Novel Heterocyclic Derivatives as In Vitro Cytotoxic Agents

2,3‐Diaryloxirane‐2,3‐dicarbonitriles have employed in heterocyclic synthesis in many organic reactions. Authors highlight its use as intermediate in the synthesis of various organic compounds through the reaction with different nitrogen nucleophiles as methyl hydrazine, thiourea, thiosemicarbazide, methylglycinate, and others to furnish new heterocyclic derivatives. They are also used as key starting materials to construct some important heterocycles. Structures of all newly synthesized products are substantiated by studying their micro analytical and spectral data. Some of newly synthesized compounds were evaluated for their in vitro cytotoxic effects against a panel of three human tumor cell lines, namely, Hep‐G2, Hela, and MCF‐7. Most of the newly synthesized compounds ( 1a , 2a , 2d , 3 , 4 , 5 , 6a , 6c , 6d , 7a , and 7b ) inhibited cell proliferation with IC₅₀ values in range of 0.52–5.21 μΜ. For activity against HepG2 cell line, compounds 5 , 6a , 6d , and 7b emerged as the most active members. The Hela cell line showed highest sensitivity toward compounds 2a , 2d , and 6c whereas compounds 2d and 6c showed the highest inhibitory activity against MCF‐7 cell line.     

Chromenol Derivatives as Novel Antifungal Agents: Synthesis,In Silico and In Vitro Evaluation

Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a–3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1–184.2 and 71.3–199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays.     

Novel,One-Pot,Three-Component,Regioselective Synthesis of Fluorine-Containing Thiazole and Bis-3H-thiazole Derivatives Using Polyvinyl Pyridine as Heterogeneous Catalyst,and Evaluation of Their Antibacterial Activity

A convenient, one-pot, three-component regioselective synthesis of novel 2,2′-(1,4-phenylene)-bis-(3-aryl-2-substituted imino-4-aryl-3H-thiazole) derivatives from 1,4-phenylene diisothiocyanate, aryl amines, and various phenacyl bromide, and also the regioselective synthesis of 3-alkyl-2-(aryl imino)-4-cyclopropyl-5-(2′-fluorophenyl)-thiazole derivatives from alkylisothiocyanate, aryl amines, and 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone in the presence of poly-4-vinyl pyridine as heterogenous basic catalyst are described. This efficient method produced the products at room temperature with excellent yields (82–96%). The structures of all products were characterized by spectral and elemental analyses. The antimicrobial activity of the synthesized compounds was evaluated against Salmonella enterica, Micrococcus luteus, Bacillus subtilis, and Pseudomonas aeruginosa.     

新型氢表雄酮C3酯类衍生物的合成及体外抗肿瘤活性评价

以去氢表雄酮(DHEA)为原料和不同的肉桂酸酯化得到11个新的去氢表雄酮C3酯类衍生物2a～2k,产率为50%～90%;DHEA与相应的苯甲醛通过羟醛缩合反应,再与不同的肉桂酸酯化得到11个新的含有(E)-16-(2-氯亚苄基)的去氢表雄酮的酯类衍生物4a～4k,产率为50%～80%。其结构经¹H NMR和ESI-MS结构表征;采用SRB法评价了在50 μM浓度下对人乳腺癌细胞（MCF-7）、人肝癌细胞（Huh-7）的体外增殖抑制活性。结果表明DHEA对两种细胞没有明显抑制作用,但是2和4系列均显示有一定的抑制活性。      

Novel One-Pot Synthesis of Functionalized (Z)-2-Arylvinyl Bromides

A novel and versatile one-pot synthesis of functionalized (Z)-2-arylvinyl bromides was developed. The new procedure involved microwave-induced debrominative decarboxylation of cinnamic acid dibromide with Et₃N and subsequent esterification in the presence of dicyclohexyl carbodiimide (DCC) and dimethyl-aminopyridine (DMAP).     

An Extensive Pharmacological Evaluation of New Anti-Cancer Triterpenoid (Nummularic Acid) from Ipomoea batatas through In Vitro,In Silico,and In Vivo Studies

Prostate cancer (PCa) is the most common cancer in men, accounting for approximately 10% of all new cases in the United States. Plant-derived bioactive compounds, such as pentacyclic triterpenoids (PTs), have the ability to inhibit PCa cell proliferation. We isolated and characterized nummularic acid (NA), a potent PT, as a major chemical constituent of Ipomoea batatas, a medicinal food plant used in ethnomedicine for centuries. In the current study, in vitro antiproliferative potential against PCa cells (DU145 and PC3) via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay; Western blot protein expression analysis; absorption, distribution, metabolism, excretion (ADME); pharmacokinetic prediction studies; and bisphenol A (BPA)-induced prostate inhibition in Sprague Dawley rats were conducted to gauge the anti-cancer ability of NA. Significant (p < 0.05 and p < 0.01) time- and dose-dependent reductions in proliferation of PCa cells, reduced migration, invasion, and increased apoptotic cell population were recorded after NA treatment (3–50 µM). After 72 h of treatment, NA displayed significant IC₅₀ of 21.18 ± 3.43 µM against DU145 and 24.21 ± 3.38 µM against PC3 cells in comparison to the controls cabazitaxel (9.56 ± 1.45 µM and 12.78 ± 2.67 µM) and doxorubicin (10.98 ± 2.71 µM and 15.97 ± 2.77 µM). Further deep mechanistic studies reveal that NA treatment considerably increased the cleavage of caspases and downstream PARP, upregulated BAX and P53, and downregulated BCL-2 and NF-κB, inducing apoptosis in PCa cells. Pharmacokinetic and ADME characterization indicate that NA has a favorable physicochemical nature, with high gastrointestinal absorption, low blood–brain barrier permeability, no hepatotoxicity, and cytochrome inhibition. BPA-induced perturbations of prostate glands in Sprague Dawley rats show a potential increase (0.478 ± 0.28 g) in prostate weight compared to the control (0.385 ± 0.13 g). Multi-dose treatment with NA (10 mg/kg) significantly reduced the prostate size (0.409 ± 0.21 g) in comparison to the control. NA-treated groups exhibited substantial restoration of hematological and histological parameters, reinstatement of serum hormones, and suppression of inflammatory markers. This multifaceted analysis suggests that NA, as a novel small molecule with a strong pharmacokinetic and pharmacological profile, has the potential to induce apoptosis and death in PCa cells.     

One-Pot,Three-Component Synthesis of 4H-Pyrans Using Cu(II) Oxymetasilicate

4H-Pyrans are synthesized through one-pot, three-component reaction of benzaldehyde, malononitrile, and ethyl acetoacetate using Cu(II) oxymetasilicate as an efficient, reusable catalyst. The procedure offers advantages in terms of better yields, short reaction times, mild reaction conditions, and reusability of the catalyst.     

Some Novel Oxadiazolyl/Azetidinyl Benzimidazole Derivatives: Synthesis and in Vitro Biological Evaluation

In a wide search program for new and efficient antimicrobial agents, a series of oxadiazole/azetidinone-incorporated benzimidazoles have been synthesized and evaluated against different Gram-positive and Gram-negative bacteria. Derivatives having long alkyl chain on the oxadiazole/azetidinone moiety with three or more carbon atoms have shown less antibacterial activity.     

Design,Synthesis and In Vitro Antitubercular Evaluation of Isatin‐ciprofloxacin Hybrids with Hydrogen Bonding Capacity

A series of novel isatin‐ciprofloxacin hybrids inhaling oxime, semicarbazone, and thiosemicarbazone groups with hydrogen bonding capacity were designed, synthesized, and evaluated for their in vitro antitubercular activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant‐TB (MDR‐TB). All hybrids endowed with potential activities against the tested MTB H37Rv and MDR‐TB strains with minimum inhibitory concentration (MIC) in a range of 0.20 to 128 μg/mL. In particular, the most active hybrid 5e (MIC: 0.20 and 0.5 μg/mL) was four and two times more active than the parent ciprofloxacin (MIC: 0.78 μg/mL) and rifampicin (MIC: 0.39 μg/mL) against MTB H37Rv, and 4–>256 times more potent than the three references ciprofloxacin (MIC: 2.0 μg/mL), rifampicin (MIC: 32 μg/mL), and isoniazid (>128 μg/mL) against MDR‐TB. Thus, this kind of hybrids holds great promise as future anti‐TB agents against both drug‐sensitive and drug‐resistant MTB strains infection.     

Design and Synthesis of Some New Furan-Based Derivatives and Evaluation of In Vitro Cytotoxic Activity

New furan-based derivatives have been, designed, synthesized, and evaluated for their cytotoxic and tubulin polymerization inhibitory activities. DNA flow cytometric study of pyridine carbohydrazide 4 and N-phenyl triazinone 7 demonstrated G₂/M phase cell cycle disruptions. Accumulation of cells in the pre-G1 phase and positive annexin V/PI staining, which may be caused by degeneration or fragmentation of the genetic components, suggested that cell death occurs via an apoptotic cascade. Furthermore, compounds 4 and 7 had a strong pro-apoptotic impact through inducing the intrinsic mitochondrial mechanism of apoptosis. This mechanistic route was verified by an ELISA experiment that indicated a considerable rise in the levels of p53 and Bax and a drop in the level of Bcl-2 when compared with the control.     

原位羟基化2,2′-联吡啶类配体及其新颖的铜(Ⅰ)和混价铜(I,Ⅱ)超分子构筑的合成

本文利用水热法合成了两个新型一价铜配合物[Cu2(ophen)2]·H2O的类同质多晶结构(1a和1β)和一个混合价的铜配合物[Cu2(obpy)2(NO3)·H2O(2).晶体结构分析表明:1a显现出于无水的类似物[Cu2(ophen)2]相同的堆积方式,1β则形成出新奇的空间堆积.混合价化合物2是完全离域的,通过氢键集聚体[(H2O)2(NO3-)2]将两个[Cu2(obpy)2]+单元连接起来形成哑铃状的四核结构.