Review ArticleNaphthalene Combretastatin Analogues: Synthesis,Cytotoxicity and Antitubulin Activity

Synthesis and evaluation of new combretastatin analogues with varied modifications on the bridge and the aromatic rings, have shown that the 2-naphthyl moiety is a good surrogate for the 3-hydroxy-4-methoxyphenyl (B-ring) of combretastatin A-4. Other bicyclic systems, such as 6(7)-quinolyl and 5-indolyl, can replace the B-ring, but they produce less potent analogues in the cytotoxicity and tubulin polymerization inhibition assays. Other modifications are detrimentral for the potency of the studied analogues. The 2-naphthyl combretastatin 53 and the related 6-quinolyl combretastatin 106 analogues are the most potent among the derivatives of this type, whereas 92 and 95 are the most potent among the naphthalene derivatives with a heterocycle in the bridge. Previous and new results in this family of combretastatin analogues are discussed.     

Synthesis of N-Glycosylated Pyridines as New Antiviral Agents

Abstract

A series of 3-cyanopyridine glycosides have been synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV) replication in MT-4 cells. Among the 3-cyanopyridine glycosides 6-(p-methylphenyl) and 6-(p-aminophenyl) were the most selective inhibitors of HIV replication.     

Synthesis of N-Glycosylated Pyridiines as New Antimetabolite Agents

Abstract

Condensation of cyanoacetamide and cyanothioacetamide with the sodium salts of a-(hydroxymethylene)alkanones afforded the pyridine-2(1H)-ones and their corresponding thiones 3. Compounds 3 served as a key intermediates for the synthesis of N-glycosylated pyridines.     

Tricyclic GyrB/ParE (TriBE) Inhibitors: A New Class of Broad-Spectrum Dual-Targeting Antibacterial Agents

Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.     

抗溃疡性结肠炎新药IPSALAZIDE的合成

以对硝基苯甲酸为原料,经氯化后,被氨基乙酸取代,得到对硝基苯甲酰氨基乙酸,再经还原,重氮化后,与水杨酸偶合,合成了抗溃疡性结肠炎新药－５［［４－［（羧甲基）甲酰氨］苯］偶氮基］水杨酸（Ｉｐｓａｌａｚｉｄｅ）。并做了红外光谱鉴定。     

抗溃疡性结肠炎新药—Balsalazide的合成

以对硝基苯甲酸为原料,经氯化后,被β—氨基丙酸取代,得到对硝基苯甲酰—β—氨基丙酸,再经还原、重氮化后,与水杨酸偶合,合成了抗溃疡性结肠炎新药—５—〔［４［（β－羧乙基）甲酰氨］苯］偶氮基〕水杨酸（Ｂａｌｓａｌａｚｉｄｅ）,并做了红外光谱鉴定。     

Synthesis of Some New Nucleoside Analogues as Potential Antiviral Agents

Abstract

A novel series of pyrimidine nucleoside analogues was synthesized. 2,3-Dideoxy-2,3-anhydro-β-D-lyxofuranose was opened by sodium azide to give the corresponding azido compound, which was reduced by lithium aluminium hydride to lead to 2,3-dideoxy-2,3-epimino-β-D-ribofuranose. Pyrimidine bases were glycosylated with this synthon to give potential antiviral molecules: 1-(2,3-dideoxy-2,3-epimino-β-D-ribofuranosyl)pyrimidines.     

Design,Synthesis, and Molecular Docking Studies of Some New Quinoxaline Derivatives as EGFR Targeting Agents

Russian Journal of Bioorganic Chemistry - The synthesis of some new quinoxaline derivatives (IVa–n) and their structure determination using 1H NMR, 13C NMR and mass spectral analysis...     

Reactivity Models of 1-N-Vinyluracil and Synthesis of a New Class of Potential Antiviral Agents by the Use of 1,3-Dipolar Cycloaddition Reactions

Abstract

By the use of a convergent approach based on 1,3-dipolar cycloaddition reactions between N-protected formylnitrones generated in situ and 1-N-vinyluracil, a new class of 4′-aza-analogues of 2′,3′-dideoxynucleosides is synthesized. Competitive reaction for the endocyclic bond of uracil also brings to a new isoxazolidine derivative fused with the pyrimidine nucleus.     

A New Approach to the Synthesis of Benzothiazole,Benzoxazole, and Pyridine Nucleosides as Potential Antitumor Agents

Abstract

A modified nitrogen and sulfur glycosylation reaction involving benzothiazole benzoxazole and pyridine nucleoside bases with furanose and pyranose sugars are described. Conformational analysis has been studied by homo- and heteronuclear two-dimensional NMR methods (2D DFQ-COSY, HMQC and HMBC). The N and S sites of glycosylation were determined from the ¹H, ¹³C heteronuclear multiple-quantum coherence (HMQC) experiments. All the deprotected nucleosides were tested for their potential antitumor activity.     

Synthesis,Biological Evaluation,and Molecular Modeling Studies of New 1,3,4-Thiadiazole Derivatives as Potent Antimicrobial Agents

In this work, the synthesis, characterization, and biological activities of a new series of 1,3,4-thiadiazole derivatives were investigated. The structures of final compounds were identified using ¹H-NMR, ¹³C-NMR, elemental analysis, and HRMS. All the new synthesized compounds were then screened for their antimicrobial activity against four types of pathogenic bacteria and one fungal strain, by application of the MIC assays, using Ampicilin, Gentamycin, Vancomycin, and Fluconazole as standards. Among the compounds, the MIC values of 4 and 8 μg/mL of the compounds 3f and 3g , respectively, are remarkable and indicate that these compounds are good candidates for antifungal activity. The docking experiments were used to identify the binding forms of produced ligands with sterol 14-demethylase to acquire insight into relevant proteins. The MD performed about 100 ns simulations to validate selected compounds’ theoretical studies. Finally, using density functional theory (DFT) to predict reactivity, the chemical characteristics and quantum factors of synthesized compounds were computed. These results were then correlated with the experimental data. Furthermore, computational estimation was performed to predict the ADME properties of the most active compound 3f .     

Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents

Currently available chemotherapeutic treatments for blood cancers (leukemia) usually have strong side effects. More selective, efficient, and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12aS)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC-SUP, UM-UC-3, KU-19-9), colon (LoVo), and breast (MCF-7, MDA-MB-231) cancer representatives, as well as two leukemic cell lines (MV-4-11, CCRF-CEM) and normal murine fibroblasts (Balb/3T3) as reference cell line. Three of the seven newly-obtained compounds ((12aS)-8-bromo-2-(3-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, (12aS)-8,9-dimethoxy-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione and (12aS)-8-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, showed enhanced activity and selectivity toward the leukemic MV-4-11 cell lines when compared to our previously reported compounds, with IC₅₀ values in the range of 2.9–5.6 μM. Additionally, (12aS)-9-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione exhibited a strong cytotoxic effect against the leukemic CCRF-CEM (IC₅₀=6.1 μM) and MV-4-11 (IC₅₀=11.0 μM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC₅₀=31.8–55.0 μM) and very weak cytotoxic effect toward the Balb/3T3 reference cell lines. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV-4-11 cells by measuring caspase-3 activity. We also established the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione on the activity of the cancer-associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (R) and (S) enantiomers had K_i values of 10–19 μM. The obtained results showed that the tested compounds exhibited a selective antileukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies.     

A Newer Method of the N-Acylation of Some Lactams via N-Trimethylsilyl Lactams

A newer method of the N-acylation of lactams via N-trimethylsilyl lactams is described.     

New Combretastatin Analogs as Anticancer Agents: Design,Synthesis, Microtubules Polymerization Inhibition,and Molecular Docking Studies

A new series of 4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives were synthesized as analogs for the anticancer drug combretastatin A-4 ( CA-4 ) and characterized using FT-IR, ¹H-NMR, ¹³CNMR, and HR-MS techniques. The new CA-4 analogs were designed to meet the structural requirements of the highest expected anticancer activity of CA-4 analogs by maintaining ring A 3,4,5-trimethoxyphenyl moiety, and at the same time varying the substituents effect of the triazole moiety (ring B ). In silico analysis indicated that compound 3 has higher total energy and dipole moment than colchicine and the other analogs, and it has excellent distribution of electron density and is more stable, resulting in an increased binding affinity during tubulin inhibition. Additionally, compound 3 was found to interact with three apoptotic markers, namely p53, Bcl-2, and caspase 3. Compound 3 showed strong similarity to colchicine , and it has excellent pharmacokinetics properties and a good dynamic profile. The in vitro anti-proliferation studies showed that compound 3 is the most cytotoxic CA-4 analog against cancer cells (IC₅₀ of 6.35 μM against Hep G2 hepatocarcinoma cells), and based on its selectivity index (4.7), compound 3 is a cancer cytotoxic-selective agent. As expected and similar to colchicine , compound 3 -treated Hep G2 hepatocarcinoma cells were arrested at the G2/M phase resulting in induction of apoptosis. Compound 3 tubulin polymerization IC₅₀ (9.50 μM) and effect on V_max of tubulin polymerization was comparable to that of colchicine (5.49 μM). Taken together, the findings of the current study suggest that compound 3 , through its binding to the colchicine-binding site at β-tubulin, is a promising microtubule-disrupting agent with excellent potential to be used as cancer therapeutic agent.     

New Diclofenac Derivatives as Anti-Microbial,Anti-Inflammatory Agents: Design,Synthesis, Biological Screening,and Molecular Docking Study

Russian Journal of Bioorganic Chemistry - Diclofenac is considered one of the best drugs used as anti-inflammatory agent, so in the present work new diclofenac derivatives containing bioactive...     

New Benzopyrrole Derivatives: Synthesis and Appraisal of Their Potential as Antimicrobial Agents

A series of twenty compounds ( 23 – 42 ) were synthesized and characterized by spectral studies in order to explore newer antimicrobial compounds. The majority of the synthesized compounds reported significant antimicrobial properties against various pathogenic bacterial and fungal strains with the help of tube dilution method. Significant activities (MIC ranging from 3.9 to 15.62 μg/ml) have been shown against Gram-negative and Gram-positive bacteria with. In contrast, moderate to outstanding antibacterial activity was reported versus Gram-negative bacteria such as E. coli and P. aeruginosa along with Gram-positive bacteria such as S. aureus and B. subtilis. While antifungal activity was moderate to excellent against two fungus strains (Candida tropicalis, Candida glabrata). Compounds 25 and 34 had the utmost activity versus Gram-positive and Gram-negative bacteria too. The antifungal activity of compound 35 was comparable to that of standard. In-silico Molecular docking evaluations were performed for antibacterial and antifungal activities against the target DNA gyrase A (PDB: 1AB4) and 14 alpha-sterol demethylase enzyme (PDB: 1EA1), respectively. The dock score for typicals compounds for antibacterial and antifungal activity were −4.733 and −9.4, respectively. The three-dimensional QSAR examination was carried out by multiple linear regression (SA-MLR) with good predictive power (r2=0.9105, q2=0.8011). Establishment of several interactions between the ligand 25 and 34 and the active site of residue of both receptors, enable the ligand 25 and 34 to be fit well in the pocket of the active site, as seen in Molecular dynamics simulations analysis. Thus, data suggest that these ligands could be further explored as potential precursors to develop antimicrobial drugs.     

Antitubulin immunofluorescence studies of spermatogenesis in the mouse

Immunofluorescence staining techniques, using antibodies against tubulin molecules, have been successfully used with somatic tissue culture cells. Their application to gametogenesis, however, has been more difficult, largely due to the presence of many different cell types in such a preparation. We have circumvented this problem by counterstaining with dilute hematoxylin, a biological stain that shows excellent cellular morphology without affecting the fluorescence of the antibody. We can then photograph the same field, using either ultraviolet light or conventional bright-field microscopy. Using this approach, we have examined the entire progression of murine spermatogenesis, from spermatogonial cells through mature spermatozoa. This technique has been especially valuable in the visualization of the manchette, and has allowed a reassessment of the staging of spermatid development. In the future, the antibody/hematoxylin double-staining approach will allow a more informative examination of the effects of tubulin-active mitotic poisons on mammalian germline cells.     

新型抗肺癌转移药系列化合物的合成

本文以对氨基苯甲酸为原料,经过重氮化、偶合、成盐等反应,合成4个抗肺癌转移药,并作了红外鉴定。     

New Fluoroquinolone-1,2,4-triazoles as Potent Antibacterial Agents: Design,Synthesis, Docking Studies and in Silico ADME Profiles

Our current work is aimed at synthesizing novel substituted 1,2,4-triazolyl-fluoroquinolone analogs and study of their biological activity to find active promising molecules. The structural elucidation of the products was demonstrated by a variety of spectroscopic methods such as IR, ¹H-NMR, ¹³C-NMR, mass and elemental analysis. The newly synthesized 1,2,4-triazole derivatives were tested in vitro for their ability to inhibit the growth of seven different microbes including S. epidermidis, S. pneumoniae, S. aureus, B. subtilis, K. pneumoniae, E. coli, and P. aeruginosa. Five FQ derivatives 5d , 5e , 5h , 5j , and 5b have demonstrated good antibacterial activity against S. pneumoniae with MICs ranging from 2.5–22.0 μg/mL, while 5c , 5g reported comparable activity against P. aeruginosa with respect to the standard drugs moxifloxacin and ciprofloxacin. The possible mechanism of antibacterial activity of fluoroquinolones was investigated via molecular docking by using DNA gyrase of S. pneumoniae (3RAE). The pefloxacin derivatives also tended a good antibacterial ability based on the results of the molecular docking, ligand 5h with good binding affinity (−9.92 Kcal/mol) and binding site interactions via ValA:86, SerA:79, TyrA:82, MetA:116, AspA:78, AlaA:63, ArgA:117, ProA:112, ProA:113, AlaA:115, AlaA:114. These scaffolds were further evaluated for their ADMET and physicochemical properties by using SwissADME, ADMETlab2.0 web server as a good oral bioavailability.     

Design,Synthesis, Molecular Docking,and Cholinesterase Inhibitory Potential of Phthalimide‐Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease

A novel series of phthalimide‐dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti‐cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti‐AChE and anti‐BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h , respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug‐like properties and were able to cross the BBB.