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.     

Synthesis and antimicrobial activity of novel 2-thiazolylimino-5-arylidene-4-thiazolidinones

New 2-thiazolylimino-5-arylidene-4-thiazolidinones (compounds 4a-j), unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria, yeasts and mould. The compounds were very potent towards all tested Gram positive microorganisms (MIC ranging from 0.03 to 6 microg/mL in most of the cases) and Gram negative Haemophilus influenzae (MIC 0.15-1.5 microg/mL), whereas no effectiveness was exhibited against Gram negative Escherichia coli and fungi up to the concentration of 100 microg/mL. The 5-arylidene derivatives showed an antibacterial efficacy considerably greater than that of the parent 2-(thiazol-2-ylimino)thiazolidin-4-one 3, suggesting that the substituted and unsubstituted 5-arylidene moiety plays an important role in enhancing the antimicrobial properties of this class of compounds. The remarkable inhibition of the growth of penicillin-resistant staphylococci makes these substances promising agents also for the treatment of infections caused by microorganisms resistant to currently available drugs.     

Novel (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones as potent antimicrobial agents

New (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones, unsubstituted or carrying fluoro, bromo, methoxy, nitro, methyl and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and fungi. The compounds were very potent towards all tested microorganisms and in most cases their activity was better than that of reference drugs.     

2-Phenylaminonaphthoquinones and related compounds: Synthesis,trypanocidal and cytotoxic activities

A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds.     

<Emphasis Type="Italic">In vitro</Emphasis> antimicrobial activity of 3,4-dihydro-<Emphasis Type="Italic">s</Emphasis>-triazinobenzimidazole derivatives

Among 31 3,4-dihydro-s-triazinobenzimidazole derivatives tested 12 compounds showedin vitro antimicrobial activity against G⁺ bacteria. Best results were obtained with substances containing naphthyl or halogenated phenyl group on the triazine ring. The tested derivatives had no significantin vitro antimicrobial activity against either the used G⁻ species or fungi.     

Pyranopyrazoles as efficient antimicrobial agents: Green,one pot and multicomponent approach

Innovative therapeutic heterocycles having precisely thiadiazolyl-pyranopyrazole fragments were prepared by using the ecofriendly synthetic route. Entire compounds formed in quantitative yields. All the composites tested for their antimicrobial effectiveness against four microbial, two beneficial fungi’s and accurately measured the minimum inhibitory concentrations (MIC and MBC/MFC), along with some initial structure activity relationships (SARs) also discussed. From the biological outcomes, the motif 6f provided an outstanding activity against all six pathogens. The possible presence of a nitro substituent on this composite may undoubtedly enhance the activity. In addition, amalgams 6d, 6g and 6l displayed promising antimicrobial results. This may be justified to the presence of electron capture group attached to the benzene ring, while the combinations 6j and 6k were zero effect towards all bacterial strains. The other compounds were excellent to low antimicrobial efficiency. The intriguing point was observed that all the active compounds had in common immense antibacterial effectiveness on Gram-negative bacteria than Gram-positive one and more antifungal activity on A. niger compare to other fungus. All things considered and suggested that this outstanding green synthetic approach is used to develop biological active compounds. On top of that, biological results confirmed that these biologically energetic motifs suitable for additional preclinical examine with the aim of standing novel innovative drugs.     

Synthesis and antimicrobial activity of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines

A series of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines (1) and (2) were synthesized and evaluated for their antimicrobial activity against three representative gram-positive bacteria and two fungi. The structure–activity relationship (SAR) demonstrates that the 3- or 4-fluorophenyl component attached directly to the triazine ring was essential for activity. Of these compounds, 14, 15, and 25 demonstrated significant activity against all selected organisms compared to control. These compounds were generally nontoxic and may prove useful as antimicrobial agents.     

5-Nitroimidazole-derived Schiff bases and their copper(II) complexes exhibit potent antimicrobial activity against pathogenic anaerobic bacteria

In the present work a family of novel secnidazole-derived Schiff base compounds and their copper(II) complexes were synthesized. The antimicrobial activities of the compounds were evaluated against clinically important anaerobic bacterial strains. The compounds exhibited in vitro antibacterial activity against Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides ovatus, Parabacteroides distasonis and Fusubacterium nucleatum pathogenic anaerobic bacteria. Upon coordination to copper(II) the antibacterial activity significantly increased in several cases. Some derivatives were even more active than the antimicrobial drugs secnidazole and metronidazole. Therefore, the compounds under study are suitable for in vivo evaluation and the microorganisms should be classified as susceptible to them. Electrochemical studies on the reduction of the nitro group revealed that the compounds show comparable reduction potentials, which are in the same range of the bio-reducible drugs secnidazole and benznidazole. The nitro group reduction potential is more favorable for the copper(II) complexes than for the starting ligands. Hence, the antimicrobial activities of the compounds under study might in part be related to intracellular bio-reduction activation. Considering the increasing resistance rates of anaerobic bacteria against a wide range of antimicrobial drugs, the present work constitutes an important contribution to the development of new antibacterial drug candidates.     

New trifluoromethyl quinolone derivatives: Synthesis and investigation of antimicrobial properties

A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria, three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal activity against Aspergillus fumigatus and Aspergillus flavus.     

Ring A-seco triterpenoids with antibacterial activity from Dysoxylum hainanense

Five new ring A-seco triterpenoids, dysoxyhainic acids F-J (1-5), along with a known ring A-seco triterpenoid koetjapic acid (6) were isolated from the twigs and leaves of Dysoxylum hainanense. Their structures were established on the basis of extensive spectroscopic analysis. Antimicrobial activity of all the compounds against fungi and bacteria were tested. Compounds 2-4 and 6 exhibited significant antimicrobial activity against Gram-positive bacteria, and the antibacterial SAR (structure-activity relationship) was also briefly discussed.     

Synthesis and antimicrobial activity of novel 5-aminoimidazole-4-carboxamidrazones

A mild and simple method was developed to prepare a series of fifteen 5-aminoimidazole 4-carboxamidrazones, starting from the easily accessible 5-amino-4-cyanoformimidoyl imidazoles. The antimicrobial activity of these novel amidrazones was screened against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Pseudomonas aeruginosa) bacteria and Candida sp. (Candida albicans, Candida krusei, Candida parapsilosis). Only a subset of compounds displayed fair-moderate activity against S. aureus and E. coli but all exhibited activity against Candida sp. The three most potent antifungal compounds were further tested against Cryptococcus neoformans, Aspergillus fumigatus and three dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum gypseum). These three hit compounds strongly inhibited C. krusei and C. neoformans growth, although their activity on filamentous fungi was very weak when compared to the activity on yeasts.     

Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis: Identification of potent inhibitors of chorismate mutase (CM)

The chorismate mutase (CM) is considered as an attractive target for the identification of potential antitubercular agents due to its absence in animals but not in bacteria. A series of 3-indolylmethyl substituted pyrazolotriazinone derivatives were designed and docked into CM in silico as potential inhibitors. These compounds were efficiently synthesized using the Pd/Cu-catalyzed coupling-cyclization in a single pot involving the construction of indole ring. The methodology was later extended to the preparation of corresponding benzo analogs of pyrazolotriazinones i.e. 3-indolylmethyl substituted benzotriazinone derivatives. Several of these novel compounds showed significant inhibition of CM when tested in vitro at 30 µM. The SAR (Structure-Activity-Relationship) studies suggested that benzotriazinone moiety was more favorable over the pyrazolotriazinone ring. The two best active compounds showed IC₅₀ ∼ 0.4–0.9 µM (better than the reference/known compounds used) and no toxicity till 30 µM in vitro.     

Novel N-benzylpyridinium moiety linked to arylisoxazole derivatives as selective butyrylcholinesterase inhibitors: Synthesis,biological evaluation,and docking study

A novel series of N-benzylpyridinium moiety linked to arylisoxazole ring were designed, synthesized, and evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Synthesized compounds were classified into two series of 5a-i and 5j-q considering the position of positively charged nitrogen of pyridinium moiety (3- or 4- position, respectively) connected to isoxazole carboxamide group. Among the synthesized compounds, compound 5n from the second series of compounds possessing 2,4-dichloroaryl group connected to isoxazole ring was found to be the most potent AChE inhibitor (IC₅₀ = 5.96 µM) and compound 5j also from the same series of compounds containing phenyl group connected to isoxazole ring demonstrated the most promising inhibitory activity against BChE (IC₅₀ = 0.32 µM). Also, kinetic study demonstrated competitive inhibition mode for both AChE and BChE inhibitory activity. Docking study was also performed for those compounds and desired interactions with those active site amino acid residues were confirmed through hydrogen bonding as well as π-π and π-anion interactions. In addition, the most potent compounds were tested against BACE1 and their neuroprotectivity on Aβ-treated neurotoxicity in PC12 cells which depicted negligible activity. It should be noted that most of the synthesized compounds from both categories 5a-i and 5j-q showed a significant selectivity toward BChE. However, series 5j-q were more active toward AChE than series 5a-i.     

Enzymatic synthesis and 3-D structure of anti-proliferative acidic (MeGlcUA) xylotetrasaccharide

Anomerically free acidic xylo-oligosaccharides have shown interesting biological properties when tested against Gram-positive and Gram-negative aerobically grown bacteria, as well as against Helicobacter pylori, sarcoma-180 and other tumors. We report here a structure–activity relationship study on the role of 4-O-methyl glucuronic acid (MeGlcUA) in regulating aggregation of β-polyxylosides of (9H-fluoren-9-yl)- methanol obtained via the action of Thermotoga neapolitana xylanase. Neutral compounds from mono- to penta-β-1,4 xylosides were obtained from this biocatalyzed reaction. In addition, acidic components among products, carrying an α-1,2 4-O-methyl glucuronic acid (MeGlcUA) were also isolated. An anti-proliferative test of these compounds on human epithelial EFO 27 ovarian cancer cells indicated that the presence of MeGlcUA modulates their biological activity, while its absence induces molecular aggregation. The three-dimensional structure of the most active MeGlcUA β-polyxyloside was investigated by resorting to NOESY experiments supported by dynamic force-field calculations with/without constraints. The 3D structure is characterized by all sugars possessing a ⁴C₁ chair conformation. The MeGlcUA moiety, and the external and middle xyloses adopt a hairpin-shaped conformation, generating a non-planar arrangement of the molecule with the aromatic ring folding back toward the carbohydrate chain. Such a non-planar conformation may justify the lack of aggregation.     

Design,synthesis and antifungal activity of amide and imine derivatives containing a kakuol moiety

In continuation of our program to discover new potential antifungal agents, a series of amide and imine derivatives containing a kakuol moiety were synthesized and characterized by the spectroscopic analysis. By using the mycelium growth rate method, the target compounds were evaluated systematically for antifungal activities in vitro against four plant pathogenic fungi, and structure–activity relationships (SAR) were derived. Compounds 7d, 7e, 7h, 7i and 7r showed obvious inhibitory activity against the corresponding tested fungi at 50 μg/mL. Especially, compounds 7e and 7r displayed more potent antifungal activity against B. cinerea than that of thiabendazole (a positive control). Moreover, compound 7e also exhibited good activity against A. alternata with EC₅₀ values of 11.0 µg/mL, and the value was slightly superior to that of thiabendazole (EC₅₀ = 14.9 µg/mL). SAR analysis showed that the ether group was a highly sensitive structural moiety to the activity and the type as well as position of substituents on benzene ring could make some effects on the activity.     

Design,structural and functional characterization of a Temporin-1b analog active against Gram-negative bacteria

Background

Temporins are small antimicrobial peptides secreted by the Rana temporaria showing mainly activity against Gram-positive bacteria. However, different members of the temporin family, such as Temporin B, act in synergy also against Gram-negative bacteria. With the aim to develop a peptide with a wide spectrum of antimicrobial activity we designed and analyzed a series of Temporin B analogs.

Methods

Peptides were initially obtained by Ala scanning on Temporin B sequence; antimicrobial activity tests allowed to identify the TB_G6A sequence, which was further optimized by increasing the peptide positive charge (TB_KKG6A). Interactions of this active peptide with the LPS of E. coli were investigated by CD, fluorescence and NMR.

Results

TB_KKG6A is active against Gram-positive and Gram-negative bacteria at low concentrations. The peptide strongly interacts with the LPS of Gram-negative bacteria and folds upon interaction into a kinked helix.

Conclusion

Our results show that it is possible to widen the activity spectrum of an antimicrobial peptide by subtle changes of the primary structure. TB_KKG6A, having a simple composition, a broad spectrum of antimicrobial activity and a very low hemolytic activity, is a promising candidate for the design of novel antimicrobial peptides.

General significance

The activity of antimicrobial peptides is strongly related to the ability of the peptide to interact and break the bacterial membrane. Our studies on TB_KKG6A indicate that efficient interactions with LPS can be achieved when the peptide is not perfectly amphipathic, since this feature seems to help the toroidal pore formation process.     

N-Aminoacyl and N-hydroxyacyl derivatives of diosgenyl 2-amino-2-deoxy-β-d-glucopyranoside: Synthesis,antimicrobial and hemolytic activities

Diosgenyl 2-amino-2-deoxy-β-d-glucopyranoside is a semisynthetic saponin with antimicrobial and antitumor activities. To search for more effective analogues, N-aminoacyl and N-hydroxyacyl derivatives of this saponin were synthesized conventionally and with microwave assistance, and tested against the human pathogenic fungi and Gram-positive and Gram-negative bacteria. None of the tested compounds exhibit activity against Gram-negative bacteria. Almost all of the synthesized N-aminoacyl saponins exhibit antifungal activity and act effectively against Gram-positive bacteria, some better than the parent compound. The best acting saponins are the same size and possess sarcosine or l- or d-alanine attached to the parent glucosaminoside. Shorter and longer aminoacyl residues are less advantageous. d-Alanine derivative is the most effective against Gram positive bacteria. Structure-activity relationship (SAR) analysis indicates that the free α-amino group in aminoacyl residue is necessary for antimicrobial activities of the tested saponins. (N-Acetyl)aminoacyl and N-hydroxyacyl analogs are inactive. Measurements of the hemolytic activities demonstrate that the best acting saponins are not toxic towards human red blood cells.     

Dodecyl sorbitan ethers as antimicrobials against Gram-positive bacteria

A range of amphiphilic sorbitan ethers has been synthesized in two steps from sorbitan following an acetalization/hydrogenolysis sequence. These sorbitan ethers and the acetal intermediates have been evaluated as antimicrobials against Gram-negative and Gram-positive bacteria. No antimicrobial activity was observed for Gram-negative bacteria. However, the compounds bearing a linear dodecyl chain exhibit antimicrobial activity (MIC as low as 8 μg/mL) against Gram-positive bacteria such as Listeria monocytogenes, Enterococcus faecalis and Staphylococcus aureus. Encouraged by these preliminary results, dodecyl sorbitan was tested against a range of resistant strains and was found to be active against vancomycin-, methicillin- and daptomycin-resistant strains (MIC = 32–64 μg/mL).     

Design and synthesis of novel 2H-chromen-2-one derivatives bearing 1,2,3-triazole moiety as lead antimicrobials

A series of novel 2H-chromen-2-one derivatives decorated with 1,2,3-triazole moiety were designed and synthesized using the click reaction of azidoalkyloxy-2H-chromen-2-ones with different propargylamines. Propargylamines were obtained by alkylation of various heterocyclic amines with propargyl bromide. Newly synthesized compounds and intermediates were evaluated for their antifungal activity against four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus and Candida albicans). Antibacterial studies were also carried out against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis and Staphylococcus epidermis) and four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Klebsiella pneumoniae). In vitro, bioassay results showed that all the synthesized compounds exhibited excellent activity against fungal strains Aspergillus fumigatus, Aspergillus flavus and Candida albicans. Interestingly, all the compounds have shown even superior activity than the reference drug miconazole against Aspergillus fumigatus. Morpholine and N-acetyl piperazine containing compounds 10c and 10e have shown promising activity against various bacterial strains. Compound 10e was found to be most active against Pseudomonas aeruginosa. Based on, in silico pharmacokinetic studies, compounds 10a–e were identified as lead compounds for future investigation due to their lower toxicity, high drug score values and good oral bioavailability as per OECD guidelines.