Thermal solvent-free synthesis of chromonyl chalcones,pyrazolines and their in vitro antibacterial,antifungal activities

A facile and ecofriendly synthesis of new chromonyl chalcones 3a-b from 3-formylchromone 1 and active methyl compounds 2a-b is reported under thermal solvent-free heating condition in good yields. The chromonyl chalcones 3a-b were used as intermediates under green condition for the synthesis of new bioactive pyrazoline derivatives 4a-f. The compounds were tested for antimicrobial activity by disk diffusion assay with slight modifications against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. The investigation of antimicrobial screening revealed that compounds 3a-b and 4a-f showed antibacterial and antifungal activities.     

Design of potent fluoro-substituted chalcones as antimicrobial agents

Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercular and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone analogs (3, 4, 9–15, and 20–23) using a structure–activity relationship approach. Target compounds were evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv and antimicrobial activity against five common pathogenic bacterial and three common fungal strains. Three derivatives (3, 9, and 10) displayed significant antitubercular activity with IC₅₀ values of ≤16,760. Compounds derived from trimethoxy substituent scaffolds with monofluoro substitution on the B ring of the chalcone structure exhibited superior inhibition activity compared to corresponding hydroxy analogs. In terms of antimicrobial activity, most compounds (3, 9, 12–14, and 23) exhibited moderate to potent activity against the bacteria, and the antifungal activities of compounds 3, 13, 15, 20, and 22 were comparable to those of reference drugs ampicillin and fluconazole.     

胶州湾沉积物可培养细菌的多样性及其抑菌活性

【目的】海洋微生物在活性物质开发方面具有巨大的应用前景。为了研究胶州湾微生物的多样性和抑菌活性,选取胶州湾9个观测站点的沉积物进行了细菌多样性及抑菌活性分析。【方法】采用YPD和Z2216E培养基分离细菌,通过16S r RNA基因测序对分离菌株进行分类鉴定,继而采用牛津杯法考察分离菌株对7株指示菌的抑菌活性,最后用PCR方法筛选16株代表菌的PKSI、NRPS、CYP、Phz E和d TGD基因。【结果】从胶州湾沉积物中共分离出76株细菌,通过对16S r RNA序列分析,将其归为8个科11个属:节杆菌属、考克氏菌属、微球菌属、微杆菌属、假交替单胞菌属、Oceanisphaera、海单胞菌属、葡萄球菌属、芽孢杆菌属、硫胺素芽孢杆菌属和短芽孢杆菌属,其中分离细菌中有34株至少对1种指示菌有抑菌活性。所选取的16株菌均能检测到一种功能基因,且其中5株菌能同时检测到3种以上的功能基因。【结论】以上研究表明胶州湾海域有丰富的微生物资源,在生物活性次级代谢产物合成上有较大潜力。     

高寒特境中甸黄芪植物根际微生物物种多样性及其抗生物膜活性成分

滇西北高寒地区分布着丰富的黄芪属植物资源，该属植物“根际效应”明显，其根际微生物极具抗菌药用资源研究价值。【目的】认知滇西北高寒特境中甸黄芪根际微生物的物种多样性，探究其可培养菌株次生代谢产物的化学多样性及抗菌、抗生物膜活性。【方法】采用宏基因组和微生物纯培养方法对中甸黄芪植物根际微生物进行物种多样性分析，同时采用高效液相色谱（high performance liquid chromatography，HPLC）、超高效液相色谱-质谱联用法（ultra-performance liquid chromatography-mass spectrometry，UPLC-MS）结合“微量肉汤稀释法” “孔板法”等多级联合筛选策略综合评估可培养菌株的抗菌活性药源研究价值。【结果】对中甸黄芪根际土壤样本的微生物分类操作单元（operational taxonomic units，OTU）进行分类注释，得到22门54纲105目187科316属856种微生物，其中优势菌群为慢生根瘤菌属。纯培养共获得27属54种95株可培养菌株，包括20属33种54株细菌和7属21种41株真菌，优势属分别为芽孢杆菌属和青霉属。其中，1株细菌Pseudomonas tolaasii ZTB4和3株真菌Aspergillus tabacinus ZNF17、Lecanicillium aphanocladii ZNF15、Umbelopsis nana ZTF31的次生代谢产物具有广谱抗菌活性。同时，菌株ZTB4和ZNF17的次生代谢产物也显示出优秀的抗耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus，MRSA）生物膜活性，并已验证这2株菌株的主要活性成分分别为环脂肽类与黄酮类。【结论】中甸黄芪植物根际微生物物种多样性较为丰富，其可培养菌株次生代谢产物有较好的化学多样性和抗菌、抗生物膜活性。研究结果为我国特境特色微生物药用资源的开发利用提供理论依据。     

Synthesis,antimicrobial activity and molecular modeling study of substituted 5-aryl-pyrimido[5,4-c]quinoline-2,4-diones

A series of pyrimido[5,4-c]quinoline-2,4-dione derivatives 5a–k were synthesized in moderate yields via a thermolysis reaction of equimolar ratio of 5-arylidine-1,3-dimethylbarbituric acid derivatives 3a–d with aniline derivatives 4a–d at 150–180 °C for 1–2?h. Eight of the synthesized compounds were chosen for a primary in vitro one-dose anticancer assay performed using the full NCI 60 cell panel. Only compound 5b showed moderate GI% at the used dose (10 μM) against four of the tested cell lines corresponding to leukemia SR (GI%: 51), non small-cell lung cancer HOP-92 (GI%: 63), melanoma UACC-62 (GI%: 53) and renal cancer UO-31 (GI%: 69). On the other hand, antimicrobial screening of the whole set of the synthesized compounds was performed against three Gram +ve and two Gram ?ve bacterial strains. Results of the antimicrobial screening showed that compounds 5d, 5e, 5f, 5h and 5k have broad-spectrum antibacterial efficacy being moderately active against all the tested Gram +ve and two Gram ?ve bacteria. Also, compound 5a showed interesting results being only active against Streptococcus faecalis and both tested Gram ?ve strains viz. E. coli and P. aeruginosa. In order to compare the binding mode of the most active compounds 5e and 5f along with the inactive compound 5c we docked these compounds into the empty binding site of topoisomerase II DNA gyrase (PDB ID: 1KZN), and results were compared with the bound inhibitor Clorobiocin.     

Synthesis,antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies

Some new derivatives of substituted-4(3H)-quinazolinones were synthesized and evaluated for their in vitro antitumor and antimicrobial activities. The results of this study demonstrated that compound 5 yielded selective activities toward NSC Lung Cancer EKVX cell line, Colon Cancer HCT-15 cell line and Breast Cancer MDA-MB-231/ATCC cell line, while NSC Lung Cancer EKVX cell line and CNS Cancer SF-295 cell line were sensitive to compound 8. Additionally, compounds 12 and 13 showed moderate effectiveness toward numerous cell lines belonging to different tumor subpanels. On the other hand, the results of antimicrobial screening revealed that compounds 1, 9 and 14 are the most active against Staphylococcus aureus ATCC 29213 with minimum inhibitory concentration (MIC) of 16, 32 and 32?μg/mL respectively, while compound 14 possessed antimicrobial activities against all tested strains with the lowest MIC compared with other tested compounds. In silico study, ADME-Tox prediction and molecular docking methodology were used to study the antitumor activity and to identify the structural features required for antitumor activity.     

Staphylococcus aureus biofilm susceptibility to small and potent β2,2-amino acid derivatives

Small antimicrobial β^2,2-amino acid derivatives (Mw < 500 Da) are reported to display high antibacterial activity against suspended Gram-positive strains combined with low hemolytic activity. In the present study, the anti-biofilm activity of six β^2,2-amino acid derivatives (A1–A6) against Staphylococcus aureus (ATCC 25923) was investigated. The derivatives displayed IC₅₀ values between 5.4 and 42.8 μM for inhibition of biofilm formation, and concentrations between 22.4 and 38.4 μM had substantial effects on preformed biofilms. The lead derivative A2 showed high killing capacity (log R), and it caused distinct ultrastructural changes in the biofilms as shown by electron and atomic force microscopy. The anti-biofilm properties of A2 was preserved under high salinity conditions. Extended screening showed also high activity of A2 against Escherichia coli (XL1 Blue) biofilms. These advantageous features together with high activity against preformed biofilms make β^2,2-amino acid derivatives a promising class of compounds for further development of anti-biofilm agents.     

Synthesis,antiproliferative and antimicrobial activity of new Mannich bases bearing 1,2,4-triazole moiety

Abstract

This study presents the synthesis, antiproliferative and antimicrobial evaluation of a new series of Mannich base derivatives containing 1,2,4-triazole system. New compounds were prepared by the reaction of 4,5-disubstituted 1,2,4-triazole-3-thiones with formaldehyde and various amines. The structures of the prepared compounds were confirmed by means of ¹H NMR, ¹³C NMR and elemental analyses. Twelve compounds were evaluated for their in vitro antiproliferative activities against six chosen cancer cell lines. All synthesized compounds were screened for their in vitro antimicrobial activity by using the agar dilution technique. For 17 potentially active compounds, their antibacterial activity was confirmed on the basis of MIC (minimal inhibitory concentration) by broth microdilution method using the reference Gram-positive and Gram-negative bacterial strains.     

Screening of potential substrates or inhibitors of cytochrome P450 17A1 (CYP17A1) by electrochemical methods

The electrochemical redox reactions of the recombinant form of human cytochrome P450 17A1 (CYP17A1) were investigated. The hemoprotein was immobilized on the electrode modified with a biocompatible nanocomposite material based on the membrane-like synthetic surfactant didodecyldimethylammonium bromide (DDAB) and gold nanoparticles. Analytical characteristics of DDAB/Au/CYP17A1 electrodes were investigated using cyclic voltammetry, square wave voltammetry, and differential pulse voltammetry. Analysis of electrochemical behavior of cytochrome P450 17A1 was performed in the presence of a natural substrate, pregnenolone (1), known inhibitor, ketoconazole (2), and in the presence of synthetic derivatives of pregnenolone: acetyl pregnenolone (3), cyclopregnenolone (4), and tetrabromo-pregnenolone (5). Ketoconazole, the azole inhibitor of cytochromes P450, blocked catalytic current in the presence of the substrate, pregnenolone (1). Compounds 3–5 did not demonstrate substrate properties towards the electrode/CYP17A1 system. Compound 3 did not influence catalytic activity with pregnenolone, whereas compounds 4 and 5 demonstrated some inhibitory activity. Thus, electrochemical redox reactions of CYP17A1 may serve as an adequate substitution of the reconstituted system, which requires additional redox partners for manifestation of catalytic activity of hemoproteins of the cytochrome P450 superfamily.     

不同栽培方式的铁皮石斛根、茎中内生细菌多样性及其抑菌活性研究

[目的] 分析树干仿生栽培和大棚种植的铁皮石斛根、茎中内生细菌的组成与分布,并挖掘潜在的微生物资源及功能。[方法] 利用Illumina MiSeq高通量测序技术,对不同栽培方式铁皮石斛根、茎中免培养内生细菌丰富度及多样性进行比较分析;通过传统的内生菌分离法以及16S rRNA基因测序技术对可培养内生细菌进行分离鉴定;采用滤纸片法筛选拮抗石斛病原菌的内生菌株。[结果] 高通量测序分析中内生细菌以Pseudomonas （30.52%）为主,其次是Mycobacterium （10.22%）以及Brachybacterium （8.32%）,树干仿生栽培石斛内生细菌组成丰富度及多样性高于大棚种植,石斛根中内生细菌组成丰富度及多样性高于石斛茎。可培养内生细菌中Bacillus （18.37%）所占比例最高,其次是Curtobacterium （8.16%）,同时筛选得到8株具有抑制石斛病原菌活性的菌株。[结论] 铁皮石斛中蕴含着丰富的内生细菌资源,菌群组成和分布受其不同栽培方式和组织部位的影响。此外,筛选得到8株具有抑制病原菌活性的菌株,表明铁皮石斛内生细菌代谢产物具有抗菌活性。本试验对铁皮石斛内生细菌多样性及其抑菌活性的分析研究,为石斛内生微生物资源的后续深度挖掘以及利用提供了内生细菌资源。     

Antibacterial profiling of abietane-type diterpenoids

Abietic and dehydroabietic acid are interesting diterpenes with a highly diverse repertoire of associated bioactivities. They have, among others, shown antibacterial and antifungal activity, potentially valuable in the struggle against the increasing antimicrobial resistance and imminent antibiotic shortage. In this paper, we describe the synthesis of a set of 9 abietic and dehydroabietic acid derivatives containing amino acid side chains and their in vitro antimicrobial profiling against a panel of human pathogenic microbial strains. Furthermore, their in vitro cytotoxicity against mammalian cells was evaluated. The experimental results showed that the most promising compound was 10 [methyl N-(abiet-8,11,13-trien-18-yl)-d-serinate], with an MIC₉₀ of 60 μg/mL against Staphylococcus aureus ATCC 25923, and 8 μg/mL against methicillin-resistant S. aureus, Staphylococcus epidermidis and Streptococcus mitis. The IC₅₀ value for compound 10 against Balb/c 3T3 cells was 45 μg/mL.     

Synthesis,characterization and antimicrobial activity of novel xanthene sulfonamide and carboxamide derivatives

Xanthene intermediates 4a and 4b were obtained from the reduction of nitro xanthene derivatives 3a and 3b which were synthesized via condensation of dimedone with m-nitrobenzaldehyde and p-nitrobenzaldehyde, respectively. Then xanthene sulfonamide 6a–n, and xanthene carboxamide derivatives 8a–h were synthesized by reaction of amino xanthene 4a, 4b with sulfonyl chlorides 5a–g and acyl chlorides 7a–d. Structures of the novel amino xanthene compounds and xanthene sulfonamide/carboxamide derivatives were established by their spectral data and elemental analyses. Furthermore, all the synthesized compounds were tested in vitro for their antimicrobial activity. The results were compared with reference standard antibiotics, erythromycin and nystatin. 6c, 6f, 6m and 8b Compounds were found to display most effective antimicrobial activity against a series of bacteria and fungi.     

Studies on novel D-ring substituted steroidal pyrazolines as potential anticancer agents

An efficient and facile synthesis of 17-pyrazolinyl derivatives of pregnenolone and their evaluation as potential anticancer agents against various human cancer cell lines are reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to the corresponding benzylidine derivatives and finally the conversion of this derivative to the stable steroidal 17-pyrazoline. Various compounds 4b, 4c, 4e, 4f, 4h and 4j showed significant cytotoxic activity especially against HT-29, HCT-15, 502713 cell lines.     

Analysis of protegrin structure–activity relationships: the structural characteristics important for antimicrobial activity using smoothed amino acid sequence descriptors

Protegrin antimicrobial peptides (AMP) possess a high activity against a variety of microorganisms. In the present contribution, we analyse the structural requirements of protegrin analogues reported by Ostberg and Kaznessis (Peptides 2005; 26: 197) for having antimicrobial activity against several microbial species by using interpretable QSAR models. Models were carried out using multiple linear regression (MLR) combined with genetic algorithm (GA) and smoothed amino acid sequence properties were employed for characterizing the peptide dataset. The main advantage of smoothing process is the alteration of local amino acid properties by the properties of the amino acids in the closer neighbourhood. We report models encompassing different characteristics for describing the activities against different microbial species. Our results suggest the existence of specific mechanisms of action for protegrin analogues against different microbial species.     

Synthesis,antimicrobial and antiviral activity of substituted benzimidazoles

In the present study we have synthesized (4-nitrophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanones, (2-bromophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanone analogues (1–14) and evaluated them for their antimicrobial and antiviral potential. The results of antimicrobial screening indicated that none of the synthesized compounds were effective against the tested bacterial strains. Compounds 3, 11, 13 and compounds 5, 11, 12 were found to be active against Aspergillus niger and Candida albicans respectively, and may be further developed as antifungal agents. Furthermore, evaluation against a panel of different viruses pointed out the selective activity of compounds 5 and 6 against vaccinia virus and Coxsackie virus B4.     

Antimicrobial Activities of 3-Amino- and Polyaminosterol Analogues of Squalamine and Trodusquemine

A series of 3-amino- and polyaminosterol analogues of squalamine and trodusquemine were synthesized and evaluated for their in vitro antimicrobial properties against human pathogens. The activity was highly dependent on the structure of the different compounds involved and the best results were obtained with aminosterol derivatives 4b, 4e, 8b, 8e and 8n exhibiting minimum inhibitory concentrations (MICs) against yeasts, Gram positive and Gram negative bacteria at average concentrations of 3.12–12.5 μM.     

D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer agents: Synthesis and biological evaluation

A facile synthesis of 21-triazolyl derivatives of pregnenolone and their potential antitumour activity is reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to 21-bromo pregnenolone and finally the one-pot, two-step in situ conversion of the bromo derivative to the 21-triazolyl pregnenolone using the ‘click chemistry’ approach. These derivatives were screened for their anticancer activity against seven human cancer cell lines. The compounds especially 5a, 5b, 5c, 5e, 5g and 5h exhibited significant anticancer activity with compound 5e as the most active in this study.     

Antimicrobial agents

The antimicrobial effectivity of 32 derivatives and analogues of 10-(4-methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepine was investigated and it was found that substituents in rings A and C and in the piperazine residue affect the antimicrobial potency of the compound. The derivative with the chlorine atom in position 3 was found to be most active in suppressing microbial growth. Substitution with chlorine of the ring C in positions 6, 7 and 8 produced derivatives with highest tuberculostatic activity. The growth of Gram-negative microorganisms (with the exception ofKlebsiella pneumoniae), as well as of fungiTrichophyton mentagrophytes, Candida albicans andAspergillus niger, was not suppressed by any of the derivatives. The antimicrobial effect of the active derivatives was demonstrated on strains ofStreptococcus haemolyticus, Staphylococcus pyogenes aureus, Mycobacterium tuberculosis, Klebsiella pneumoniae andSaccharomyces pastorianus.     

Antimicrobial activity studies on some piperidine and pyrrolidine substituted halogenobenzene derivatives

The in vitro antibacterial and antifungal activities of the compounds synthesised from some 1,2,3,5-tetrahalogeno benzenes in presence of sodium piperidide and sodium pyrrolidide (2,6-dipiperidino-1,4-dihalogenobenzenes; 2,6-dipyrrolidino-1,4-dibromobenzene; 2,4,6-tripyrrolidino chlorobenzene; and 1,3-dipyrrolidino benzene) were investigated. The in vitro antimicrobial activities were screened against the standard strains: Staphylococcus aureus ATCC 25923 and Bacillus subtilis ATCC 6633 as Gram positive, Yersinia enterocolitica ATCC 1501, Escherichia coli ATCC 11230 and Klebsiella pneumoniae as Gram negative, and Candida albicans as yeast-like fungus. Compounds (3, 5, 6, 7) inhibited the growth of all the test strains at MIC values of 32–512 μg/ml. None of the four compounds (1, 2, 4, 8) studied showed antimicrobial activity against any of the test strains within the MIC range 0.25–512 μg/ml.     

Biotransformation using <Emphasis Type="Italic">Mucor rouxii</Emphasis> for the production of oleanolic acid derivatives and their antimicrobial activity against oral pathogens

The goal of this study is to produce oleanolic acid derivatives by biotransformation process using Mucor rouxii and evaluate their antimicrobial activity against oral pathogens. The microbial transformation was carried out in shake flasks at 30°C for 216 h with shaking at 120 rpm. Three new derivatives, 7β-hydroxy-3-oxo-olean-12-en-28-oic acid, 7β,21β-dihydroxy-3-oxo-olean-12-en-28-oic acid, and 3β,7β,21β-trihydroxyolean-12-en-28-oic acid, and one know compound, 21β-hydroxy-3-oxo-olean-12-en-28-oic acid, were isolated, and the structures were elucidated on the basis of spectroscopic analyses. The antimicrobial activity of the substrate and its transformed products was evaluated against five oral pathogens. Among these compounds, the derivative 21β-hydroxy-3-oxo-olean-12-en-28-oic acid displayed the strongest activity against Porphyromonas gingivalis, which is a primary etiological agent of periodontal disease. In an attempt to improve the antimicrobial activity of the derivative 21β-hydroxy-3-oxo-olean-12-en-28-oic acid, its sodium salt was prepared, and the minimum inhibitory concentration against P. gingivalis was reduced by one-half. The biotransformation process using M. rouxii has potential to be applied to the production of oleanolic acid derivatives. Research and antimicrobial activity evaluation of new oleanolic acid derivatives may provide an important contribution to the discovery of new adjunct agents for treatment of dental diseases such as dental caries, gingivitis, and periodontitis.