Studies on anti-Helicobacter pylori agents. Part 2: new cephem derivatives

The synthesis and optimization of the anti-Helicobacter pylori activity of a novel series of cephem derivatives are described. Introduction of thio-heterocyclic groups containing N- and S-atoms to the 3-position and phenyl or thienyl acetamido groups to the 7-position of the cephem nucleus dramatically improved the activity. From this series of derivatives, compound 13i was found to have extremely potent in vitro anti-H. pylori activity, superior therapeutic efficacy compared to AMPC and CAM, no cross-resistance between CAM or MNZ and low potential for causing diarrhea due to instability to beta-lactamase.     

Synthesis and anti-Helicobacter pylori activity of FR182024, a new cephem derivative

The synthesis and anti-Helicobacter pylori activity of a novel cephem derivative FR182024 (1) are described. FR182024 having a (5-methyl-1,3,4-thiadiazol-2-yl)-thio moiety at the 3-position and a phenylacetamido at the 7-position was found to have extremely potent in vitro anti-H.pylori activity, superior therapeutic efficacy to AMPC and CAM, and low potential for causing diarrhea.     

Studies on anti-Helicobacter pylori agents. Part 1: Benzyloxyisoquinoline derivatives

The synthesis and optimization of the anti-Helicobacter pylori activity of a novel series of benzyloxyisoquinoline derivatives that was discovered by a random screening process, are described. In the in vitro assay, compound 10c containing a 3-acetamido-2,6-dichlorobenzyl substituent was found to have extremely potent activity against H. pylori and no activity against other common bacteria. The anti-H. pylori activity of 10c was superior to that of amoxicillin (AMPC) (1) and clarithromycin (CAM) (2). However, 10c did not show in vivo efficacy in a mouse infection model; a feature attributed to the lack of strong bactericidal activity at short contact times.     

A novel class of selective anti-Helicobacter pylori agents 2-oxo-2H-chromene-3-carboxamide derivatives

A novel class of selective anti-Helicobacter pylori agents, 2-oxo-2H-chromene-3-carboxamide derivatives, were prepared and evaluated for their anti-bacterial activity. All synthesized compounds showed little or no activity against different species of Gram-positive and Gram-negative bacteria and against various strains of pathogenic fungi. Some of them exhibited a potent and specific inhibitory effect on the growth of H. pylori, including metronidazole-resistant strains, in the 0.0039-16 microg/mL MIC range. A cytotoxic screening by the Trypan blue dye exclusion assay was also carried out on the most active compounds as anti-H. pylori agents. Among the derivatives examined for their cytotoxic potential, a number of them induced low cytotoxic effects.     

Armeniaspirol A: a novel anti-Helicobacter pylori agent

Antibiotic resistance in Helicobacter pylori has been growing worldwide with current treatment regimens. Development of new compounds for treatment of H. pylori infections is urgently required to achieve a successful eradication therapy in the future. Armeniaspirols, a novel class of natural products isolated from Streptomyces armeniacus, have been previously identified as antibacterial agents against Gram-positive pathogens. In this study, we found that armeniaspirol A (ARM1) exhibited potent antibacterial activity against H. pylori, including multidrug-resistant strains, with MIC range values of 4–16 μg ml^-1. The underlying mechanism of action of ARM1 against H. pylori involved the disruption of bacterial cell membranes. Also, ARM1 inhibited biofilm formation, eliminated preformed biofilms and killed biofilm-encased H. pylori in a dose-dependent manner. In a mouse model of multidrug-resistant H. pylori infection, dual therapy with ARM1 and omeprazole showed efficient in vivo killing efficacy comparable to the standard triple therapy, and induced negligible toxicity against normal tissues. Moreover, at acidic pH 2.5, ARM1 exhibited a much more potent anti-H. pylori activity than metronidazole. Thus, these findings demonstrated that ARM1 is a novel potent anti-H. pylori agent, which can be developed as a promising drug lead for treatment of H. pylori infections.     

FR290581, a novel sordarin derivative: Synthesis and antifungal activity

Sordarin is a unique natural product antifungal agent that is an inhibitor of elongation factor 2. To improve biological activity, we synthesized various compounds by novel modification of the aglycone, sordaricin. As a result, we have discovered the novel sordarin derivative FR290581. This compound exhibited superior activity and a good pharmacokinetic profile, and also displayed good in vivo activity against Candida albicans.     

Antitumor agents. Part 227: Studies on novel 4'-O-demethyl-epipodophyllotoxins as antitumor agents targeting topoisomerase II

Eight novel epipodophyllotoxin derivatives (6-13), which were designed to overcome drug resistance and enhance topoisomerase II inhibition, were synthesized and evaluated. Two of these compounds (7 and 8) showed better preclinical activity profiles, including cell growth inhibition, cell killing, and in vitro topoisomerase II inhibition, as compared to the prototype molecule etoposide (1). They also retained the superior drug-resistance profile of GL-331 (4), an epipodophyllotoxin derivative currently in clinical evaluation.     

A specific anti-Helicobacter pylori agent NE2001: synthesis and its effect on the growth of H. pylori

The synthesis and anti-Helicobacter pylori activity of a novel agent NE2001, 4-(4-methylbenzyl)-4'-[guanidinomethylbenzoyloxy] biphenyl-4-carboxylate hydrochloride, are described. NE2001 had a specific inhibitory effect on the growth of H. pylori preceded by the suppression DNA synthesis in the cell. The effects of NE2001 on RNA and protein syntheses in H. pylori were also examined.     

Synthesis,selective anti-Helicobacter pylori activity,and cytotoxicity of novel N-substituted-2-oxo-2H-1-benzopyran-3-carboxamides

N-substituted-3-carboxamido-coumarin derivatives were prepared and evaluated for selective antibacterial activity against 20 isolates of Helicobacter pylori clinical strains, including five metronidazole resistant ones. Some of them possessed the best activity against H. pylori metronidazole resistant strains with MIC values lower than the drug reference (metronidazole). Furthermore, anti-inflammatory activity through the inhibition of the IL-8 production was investigated.     

Bioactive compounds of Crocus sativus L. and their semi-synthetic derivatives as promising anti-Helicobacter pylori,anti-malarial and anti-leishmanial agents

Abstract

Crocus sativus L. is known in herbal medicine for the various pharmacological effects of its components, but no data are found in literature about its biological properties toward Helicobacter pylori, Plasmodium spp. and Leishmania spp. In this work, the potential anti-bacterial and anti-parasitic effects of crocin and safranal, two important bioactive components in C. sativus, were explored, and also some semi-synthetic derivatives of safranal were tested in order to establish which modifications in the chemical structure could improve the biological activity. According to our promising results, we virtually screened our compounds by means of molecular modeling studies against the main H. pylori enzymes in order to unravel their putative mechanism of action.     

Anti-tubercular agents. Part 3. Benzothiadiazine as a novel scaffold for anti-Mycobacterium activity

In an effort to develop new and more effective therapies to treat tuberculosis, a series of benzothiadiazine 1,1-dioxide derivatives were synthesized and their in vitro activity against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare was evaluated. One of the compounds, 8c, exhibited potent anti-tubercular activity, particularly for the resistant strains and thus prompted us to investigate its in vivo profile. However, the in vivo testing in a mouse model of tuberculosis infection did not show significant anti-tubercular activity, probably because of its poor bioavailability.     

Novel echinocandin antifungals. Part 1: novel side-chain analogs of the natural product FR901379

A series of novel acylated analogs of the novel water-soluble echinocandin FR901379 have been prepared and evaluated for antifungal and hemolytic activity. A relationship between antifungal activity and lipophilicity of the acyl side chain, expressed as ClogP was demonstrated, and an analog (3c) with 5.5- to 8-fold superior in vivo activity relative to the previously disclosed 4-(n-octyloxy)benzoyl side chain analog, FR131535 obtained.     

Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).     

抗幽门螺杆菌药物的研究进展

幽门螺杆菌(Helicobacter pylori)是引起胃炎、胃和十二指肠溃疡乃至胃癌的主要致病菌。近年来,随着大量广谱抗生素的广泛应用使得耐药的幽门螺杆菌菌株呈不断上升趋势,开发高效和高选择性的抗幽门螺杆菌药物已经成为全球关注的课题。本文对近五年来文献报道的抗幽门螺杆菌药物和先导化合物分类进行简要综述,为研究开发幽门螺杆菌感染性疾病的治疗新药提供参考。     

Ligustrazine derivatives. Part 3: Design,synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents

A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities were evaluated. The results showed that compound E33 displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound E1 was found to be the most active antiplatelet aggregation agent. Structure–activity relationships were briefly discussed.     

Heterocyclic thrombin inhibitors. Part 2: quinoxalinone derivatives as novel,potent antithrombotic agents

Quinoxalinone derivatives as prototypes of dual thrombin and factor Xa inhibitors have been discovered. Nanomolar inhibition of both coagulation enzymes resulted in very potent antithrombotic activity in vitro.     

Antitumor agents. Part 232: Synthesis of cyclosulfite podophyllotoxin analogues as novel prototype antitumor agents

An 11,13-O,O'-cyclosulfite GL-331 analogue (7) was synthesized in six steps from podophyllotoxin and evaluated as a potential antitumor agent. Compound 7 was significantly cytotoxic against human tumor cell lines, but showed no inhibition against human DNA topoisomerase II in vitro. This compound represents a novel prototype of antitumor podophyllotoxin analogues.     

Antitumor agents. Part 202: novel 2'-amino chalcones: design, synthesis and biological evaluation

New 4',5',2,3,4-substituted 2'-amino chalcones were synthesized and evaluated for cytotoxicity against a panel of human tumor cell lines. Several compounds displayed significant cytotoxicity. The most promising lead molecule (10) also had high activity toward multi-drug resistant KB-VIN, and ovarian 1A9 cell lines. 2'-Amino chalcones demonstrated significantly increased antitumor activity compared with the corresponding chalcones, while, the epoxide derivatives generally showed greatly reduced activity.     

A novel fluorinated derivative of diethylstilbestrol.

The synthesis of the diethylstilbestrol (DES) derivative with fluorine atoms present in the positions ortho to the hydroxyl in each ring is described. In vitro studies in a system containing horse radish peroxidase/H2O2 demonstrate extensive oxidation of tetrafluorodiethylstilbestrol to the corresponding dienestrol derivative. Tetrafluorodiethylstilbestrol and DES had comparable in vivo uterotropic activities at a dose of 100 microgram/kg. Competitive binding experiments demonstrated 20-25 fold reduced interaction with the mouse uterine estrogen receptor. This compound may be useful as an experimental estrogen in distinguishing between the biological and toxic effects of DES.     

Structure-activity relationships of novel anti-malarial agents. Part 2: cinnamic acid derivatives

We have described compound 1 as a lead structure for a novel class of anti-malarial agents. Replacement of the 3-phenylpropionyl moiety of the lead structure 1 by a 4-propoxycinnamic acid residue resulted in a significant improvement in antimalarial activity. Compound 3q represents an important step in the development of lead structure 1 into an anti-malarial drug candidate.