Synthesis and antimicrobial evaluation of bile acid tridentate conjugates

Two series of novel bile acid tridentate conjugates with different linkers were synthesized and characterized, and their biological activities in vitro were evaluated. The procedure was straightforward and efficient to be carried out with high overall yield. The antimicrobial activity of the synthesized compounds against Saccharomyces cerevisiae, Aspergillus niger, Escherichia coli and Staphylococcus aureus was investigated in vitro. The best activity of minimal inhibitory concentrations (MICs) for 1c, 1c′, 2c and 2c′ against S. cerevisiae was up to 0.125 μg/mL.     

Substituted 2-(3′,4′,5′-trimethoxybenzoyl)-benzo[b]thiophene derivatives as potent tubulin polymerization inhibitors

The central role of microtubules in cell division and mitosis makes them a particularly important target for anticancer agents. On our early publication, we found that a series of 2-(3′,4′,5′-trimethoxybenzoyl)-3-aminobenzo[b]thiophenes exhibited strong antiproliferative activity in the submicromolar range and significantly arrested cells in the G2–M phase of the cell cycle and induced apoptosis.In order to investigate the importance of the amino group at the 3-position of the benzo[b]thiophene skeleton, the corresponding 3-unsubstituted and methyl derivatives were prepared. A novel series of inhibitors of tubulin polymerization, based on the 2-(3,4,5-trimethoxybenzoyl)-benzo[b]thiophene molecular skeleton with a methoxy substituent at the C-4, C-5, C-6 or C-7 position on the benzene ring, was evaluated for antiproliferative activity against a panel of five cancer cell lines, for inhibition of tubulin polymerization and for cell cycle effects. Replacing the methyl group at the C-3 position resulted in increased activity compared with the corresponding 3-unsubstituted counterpart. The structure–activity relationship established that the best activities were obtained with the methoxy group placed at the C-4, C-6 or C-7 position. Most of these compounds exhibited good growth inhibition activity and arrest K562 cells in the G2–M phase via microtubule depolymerization.     

Combination of 1,4-naphthoquinone with benzothiazoles had selective algicidal effects against harmful algae

A series of naphthoquinone-benzothiazole conjugates were synthesized as algicides, and their efficacies against harmful algal blooming species, such as Chattonella marina, Heterosigma akashiwo and Cochlodinium polykrikoides, were examined. The introduction of substituted benzothiazole at the C2 position of 1,4-naphthoquinone (compounds 1–9) resulted in higher algicidal activity against C. polykrikoides than the C6 conjugates (compounds 10–20). On the other hand, of the C6 conjugates, compounds 11 and 12 exhibited better algicidal activity against H. akashiwo, C. marina, and C. polykrikoides than the C2 conjugates. Further structure-activity analysis indicated that a replacement of the methoxy groups with hydroxyl groups (compounds 21–26) decreased the algicidal activity significantly. Among the various synthetic naphthoquinonebezothiazole conjugates tested, compound 12 was found to affect the most significant decrease in the level of C. polykrikoides growth, with an IC₅₀ of 0.19 μM. Compound 11 was found to be the most potent inhibitor against H. akashiwo and C. polykrikoides, with IC₅₀ values of 0.32 and 0.12 μM, respectively. Overall, these results highlight a possible method for controlling and inhibiting red tide forming algae using NQ derivatives.     

Antimicrobial activities of some synthesized 1-(3-(2-methylphenyl)-4-Oxo-3<Emphasis Type="Italic">H</Emphasis>-quinazolin-2-yl-4-(substituted)thiosemicarbazide derivatives

The substituted thiosemicarbazide moiety was placed at the C-2 position and 2-methylphenyl group at N-3 position of quinazoline ring and obtained compounds were tested for their antitubercular activities and antibacterial activities against selected gram-positive and gram-negative bacteria. The target compounds 1-(3-(2-methylphenyl)-4-oxo-3H-quinazolin-2-yl)-4-(substituted) thiosemicarbazides were obtained by the reaction of 2-hydrazino-3-(2-methylphenyl) quinazolin-4(3H)-one with different dithiocarbamic acid methyl ester derivatives. All synthesized compounds were also screened for their antimicrobial activity against selective gram-positive and gram-negative bacteria by agar dilution method. Among the series, 1-[3-(2-methylphenyl)-4-oxo-3H-quinazolin-2-yl]-4-[4-chlorophenyl]-thiosemicarbazide exhibited the most potent activity against S. typhi, E. coli, and B. subtilis, while 1-[3-(2-methylphenyl)-4-oxo-3H-quinazolin-2-yl]-4-[4-nitrophenyl]-thiosemicarbazide was the most potent against E. coli, B. subtilis, P. aeruginosa, S. typhi, and S. flexneri. These two compounds exhibited the antitubercular activity at the minimum concentration (3 μg/mL) that offered potential for further optimization and development of new antitubercular agents. The obtained results demonstrated promising antimicrobial and antitubercular activities of the synthesized quinazoline compounds which could be used as new scaffolds for improving their antimicrobial activity.     

Peptide dendrimers as antifungal agents and carriers for potential antifungal agent—N3‐(4‐methoxyfumaroyl)‐(S)‐2,3‐diaminopropanoic acid—synthesis and antimicrobial activity

A series of peptide dendrimers and their conjugates with antimicrobial agent FMDP (N³‐(4‐methoxyfumaroyl)‐(S)‐2,3‐diamino‐propanoic acid) were synthesized. The obtained compounds were tested for the antibacterial and antifungal activity. All novel dendrimers displayed much better activity against the tested strains than FMDP itself. Moreover, their conjugates with FMDP also exhibited antimicrobial activity. The most promising molecules were tested against a broad selection of fungal strains. The analysis of their antifungal properties indicates that the examined molecules are efficient growth inhibitors of fluconazole‐resistant hospital‐acquired strains. Moreover, an application of amphiphilic branched peptides such as FMDP carriers suggests that transport mechanism involves more likely the cell membrane perturbation than the mediation of the specific transport proteins. The activity of obtained compounds strongly depends on the specific structure of the molecule.     

Synthesis, characterization and antimicrobial activity of new silver complexes with N-heterocyclic carbene ligands

Synthesis, structure, and antimicrobial studies of silver complexes of N-heterocyclic carbene (NHC) are reported. All the silver-NHC complexes (1a-f) were prepared from the benzimidazolium salts by the reactions with Ag₂O in dichloromethane as a solvent at room temperature. The new compounds characterized by ¹H NMR, ¹³ C NMR, IR and elemental analysis techniques which support the proposed structures. Chloro[1-(2,4,6-trimethylbenzyl)-3-(methoxyethyl)benzimidazol-2-ylidene]silver(I) complex was structurally characterized by single-crystal X-ray diffraction. A series of new Ag-NHC complexes were screened for their in vitro antimicrobial activity against a variety of Gram-positive and Gram-negative bacteria as well as for their antifungal activity against a Candida albicans and Candida tropicalis.     

25-Methoxylprotopanaxadiol derivatives and their anti-proliferative activities

(20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH₃-PPD) is a dammarane-type sapogenin showing anti-proliferative potential. In our study, two series of analogs substituted at the C-3 or C-3 and C-12 positions with fatty acids were prepared conveniently. The cytotoxic activity of these compounds was evaluated using four different human tumor cell lines (A549, Hela, HT-29 and MCF-7) and a normal cell line (IOSE144). As compared with 25-OCH₃-PPD, compounds 1a, 1b, 2a and 2b showed better anti-proliferative activities against all tumor cell lines and all the derivatives, with low toxicities in the normal cell line. Compound 1a (C-3 monoformiate) exhibited the strongest activity with the IC₅₀ value of 5.2 μM towards HT29 cells. The results indicated that the difference in the substituents may affect the anti-proliferative activity of the compounds. The longer the side chain of 25-OCH₃-PPD is, the lower the anti-proliferative activity would be. This information may be useful for evaluating the structure–activity relationship of other dammarane-type sapogenins and for development of novel antineoplastic agents.     

Synthesis of 3'-azido-3'-deoxythymidine (AZT)--Cinchona alkaloid conjugates via click chemistry: Toward novel fluorescent markers and cytostatic agents

Novel nucleoside-Cinchona alkaloid conjugates were synthesized using ‘click’ chemistry approach based on the copper(I) catalyzed Huisgen azide-alkyne cycloaddition. Two series of conjugates were prepared employing 3′-azido-3′-deoxythymidine (AZT) as the azide component and the four 10,11-didehydro Cinchona alkaloids as well as their 9-O-propargyl ethers as the alkyne components. All obtained conjugates showed strong fluorescence emission and some of them exhibited marked cytotoxic activity in vitro.     

Synthesis and evaluation of biological activity for dual-acting antibiotics on the basis of azithromycin and glycopeptides

One of the promising directions of the combined approach is the design of dual-acting antibiotics – heterodimeric structures on the basis of antimicrobial agents of different classes. In this study a novel series of azithromycin-glycopeptide conjugates were designed and synthesized. The structures of the obtained compounds were confirmed using NMR spectroscopy and mass spectrometry data including MS/MS analysis. All novel hybrid antibiotics were found to be either as active as azithromycin and vancomycin against Gram-positive bacterial strains or have superior activity in comparison with their parent antibiotics. One compound, eremomycin-azithromycin conjugate 16, demonstrated moderate activity against Enterococcus faecium and Enterococcus faecalis strains resistant to vancomycin, and equal to vancomycin’s activity for the treatment of mice with Staphylococcus aureus sepsis.     

Synthesis and evaluation of 1,3,4-oxadiazole derivatives for development as broad-spectrum antibiotics

The reality and intensity of antibiotic resistance in pathogenic bacteria calls for the rapid development of new antimicrobial drugs. In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. Because trans-translation is absent in eukaryotes but necessary to avoid ribosomal stalling and therefore essential for bacterial survival, it is a promising target either for novel antibiotics or for improving the activities of the protein synthesis inhibitors already in use. Oxadiazole derivatives display strong bactericidal activity against a large number of bacteria, but their effects on trans-translation were recently questioned. In this work, a series of new 1,3,4-oxadiazole derivatives and analogs were synthesized and assessed for their efficiency as antimicrobial agents against a wide range of gram-positive and gram-negative pathogenic strains. Despite the strong antimicrobial activity observed in these molecules, it turns out that they do not target trans-translation in vivo, but they definitely act on other cellular pathways.     

Anti-tubercular agents. Part 8: Synthesis,antibacterial and antitubercular activity of 5-nitrofuran based 1,2,3-triazoles

A series of 5-nitrofuran–triazole conjugates were synthesized and evaluated for their antimicrobial activity against both Gram-positive and Gram-negative bacterial strains. All the compounds exhibited promising inhibition towards Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 8a, 8b, 8e, 8f, 8h are most active among the series exhibiting MIC value of 1.17 μg/ml against different bacterial strains. The bactericidal activity is found to be in accordance with the bacterial growth inhibition data. Compound 8e was found to be equipotent to the standard drug Ciprofloxacin displaying MBC value of 1.17 μg/ml against the bacterial strain Bacillus subtilis. The compounds have also demonstrated promising antibacterial activity against the resistant strain MRSA and were found to be effective inhibitors of biofilm formation. The compound 8b exhibited excellent anti-biofilm activity with IC₅₀ value as low as 0.8 μg/ml. These conjugates were also screened for antitubercular activity against Mycobacterium tuberculosis H₃₇Rv strain. Compound 8e showed promising antitubercular activity with MIC value of 0.25 μg/ml. Most of these compounds are less toxic to normal mammalian cells than the widely used antibacterial drug Ciprofloxacin.     

The novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea: synthesis, anti-inflammatory, antibacterial and antifungal activity evaluation

A series of novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of biological interest were prepared by sequential Bigineli’s reaction, reduction followed by reaction of resulting amines with different arylisocynates. All the synthesized (1-23) compounds were screened against the pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological activity evaluation study reveled that among all the compounds screened, compounds 12 and 17 found to have promising anti-inflammatory activity (68-62% TNF-α and 92-86% IL-6 inhibitory activity at 10 μM). Interestingly compounds 3, 4, 5, 6, 15, 22 and 23 revealed promising antimicrobial activity at MIC of 10-30 μg/mL against selected pathogenic bacteria and fungi.     

Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors

This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC₅₀ of 0.88?µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH₃O group or CF₃O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation.     

Design,synthesis and antimalarial/anticancer evaluation of spermidine linked artemisinin conjugates designed to exploit polyamine transporters in Plasmodium falciparum and HL-60 cancer cell lines

A series of artemisinin–spermidine conjugates designed to utilise the upregulated polyamine transporter found in cancer cells have been prepared. These conjugates were evaluated against human promyelocytic leukaemia HL-60 cells and chloroquine-sensitive 3D7 Plasmodium falciparum and several show promising anticancer and antimalarial activity. Although some limitations in this vector-based approach are apparent, a number of high potency Boc-protected analogues were identified with activity against malaria parasites as low as 0.21 nM.     

Synthesis and cytotoxicity of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A

A series of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A were designed and synthesized in 7 steps. Most compounds exhibited comparable cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780) to natural product ceratamine A. Compound 1k, bearing methoxy group at C-14, C-15 and C-16, showed the best in vitro cytotoxicity, which was better than ceratamine A. The structure and activity relationships study showed that the benzyloxymethyl group on N-3 played an important role on the cytotoxicity.     

Nematicidal activity against Aphelenchoides besseyi and Ditylenchus destructor of three biflavonoids,isolated from roots of Stellera chamaejasme

Aphelenchoides besseyi and Ditylenchus destructor can cause serious problems for a number of important agricultural crops and vegetables. In this study, the ethanol extract of Stellera chamaejasme L. roots showed strong nematicidal activity against Aphelenchoides besseyi and Ditylenchus destructor. By using a bioactivity-driven fractionation, three biflavonoids were isolated from the extract and their structures were identified by mass and nuclear magnetic resonance spectral data. Nematicidal activity bioassays revealed that isoneochamaejasmin A had the strongest nematicidal activity against A. besseyi and D. destructor with LC₅₀ values of 2.32 and 0.18?mM at 72?h, respectively. Chamaejasmenin B displayed weaker nematicidal activity against A. besseyi with an LC₅₀ value of 3.94?mM at 72?h. Neochamaejasmin B induced the lowest mortality against D. destructor with an LC₅₀ values of 15.6?mM at 72?h. These results suggested that the kind and position of substitutions and the relative configuration of 2-H/3-H and 2”-H/3”-H could be considered as important factors responsible for the nematicidal activity of these purified C-3/C-3″ biflavonoids.     

Zinc oxide nanoparticle inhibits the biofilm formation of <Emphasis Type="Italic">Streptococcus pneumoniae</Emphasis>

Biofilms are structured consortia of microbial cells that grow on living and non living surfaces and surround themselves with secreted polymers. Infections with bacterial biofilms have emerged as a foremost public health concern because biofilm growing cells can be highly resistant to both antibiotics and host immune defenses. Zinc oxide nanoparticles have been reported as a potential antimicrobial agent, thus, in the current study, we have evaluated the antimicrobial as well as antibiofilm activity of zinc oxide nanoparticles against the bacterium Streptococcus pneumoniae which is a significant cause of disease. Zinc oxide nanoparticles showed strong antimicrobial activity against S. pneumoniae, with an MIC value of 40 μg/ml. Biofilm inhibition of S. pneumoniae was also evaluated by performing a series of experiments such as crystal violet assay, microscopic observation, protein count, EPS secretion etc. using sub-MIC concentrations (3, 6 and 12 µg/ml) of zinc oxide nanoparticles. The results showed that the sub-MIC doses of zinc oxide nanoparticles exhibited significant anti-biofilm activity against S. pneumoniae, with maximum biofilm attenuation found at 12 μg/ml. Taken together, the results indicate that zinc oxide nanoparticles can be considered as a potential agent for the inhibition of microbial biofilms.     

Semisynthesis,cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives

In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC₅₀?=?3.4?µM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC₅₀?>?400?µM), showing selectivity towards parasites (selectivity index?>?117.47). In combination with artemisinin, compound 7b showed an additive effect (CI?=?1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of ?7.02?kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC₅₀?=?93?µM) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3β-butanoyl betulinic acid on Plasmodium may be related to other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources.     

Structure–activity relationship of potent antimicrobial peptide analogs of Ixosin-B amide

There is a great urgency in developing a new generation of antibiotics and antimicrobial agents since the bacterial resistance to antibiotics have increased dramatically. A series of overlapped peptide fragments of Ixosin-B, an antimicrobial peptide with amino acid sequence of QLKVDLWGTRSGIQPEQHSSGKSDVRRWRSRY, was designed, synthesized and examined for their antimicrobial activities against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. A potent 11-mer peptide TSG-8-1, WWSYVRRWRSR-amide, was developed, which exhibited antimicrobial activity against E. coli and S. aureus while very little hemolytic activity in human erythrocytes was observed at high dose level. This peptide could be further modified for the development of a potent antimicrobial agent in the future.     

Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents

The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (1) and 3′,4,4′,5′-tetramethoxychalcone (2) were selected as parent chalcones since they were found to be efficient anti-proliferative agents on various cancer cells. A series of ten chalcone-polyamine conjugates was obtained by reacting carboxychalcones with different polyamine tails. Chalcones 1 and 2 showed a strong cytotoxic activity against two prostatic cancer (PC-3 and DU-145) and two colorectal cancer (HT-29 and HCT-116) cell lines. Then, chalcone-spermine conjugates 7d and 8d were shown to be the most active of the series and could be considered as promising compounds for colon and prostatic cancer adjuvant therapy.