Microwave assisted nano (ZnO–TiO2) catalyzed synthesis of some new 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine as antimicrobial agents

Combined nano zinc oxide and titanium dioxide [nano (ZnO–TiO₂)] has been reported first time for the synthesis of novel series of 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine. All the synthesized compounds (7a–7m) are novel and were screened for their antimicrobial activity against four different strains like Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis and antifungal activity was determined against two strains Candida albicans and Aspergillus niger. SAR for the newly synthesised derivatives has been developed by comparing their MIC values with ampicillin, ciprofloxacin and miconazole for antibacterial and antifungal activities, respectively. Among the synthesized compounds, 2,6 dichlorophenyl analogue (7f), 4 fluorophenyl analogue (7k) and 2,6 dichlorophenyl analogue (7l) shows promising antibacterial as well as antifungal activity whereas thiophene substituted compound (7j) shows promising antibacterial activity.     

Cadiolides J–M,antibacterial polyphenyl butenolides from the Korean tunicate Pseudodistoma antinboja

Activity-guided fractionations of the tunicate Pseudodistoma antinboja yielded four new compounds of the cadiolide class (cadiolides J–M, 1, 3–5) along with a known one (cadiolide H, 2). The structures were defined by spectroscopic methods including X-ray crystallographic analysis. These compounds were evaluated for their antibacterial activity and exhibited potent antibacterial activity against all of the drug resistant strains tested with MICs comparable to those of marketed drugs such as vancomycin and linezolid.     

Amino ether analogues of 4,4′-dihydroxy-3-methoxy-6,7′-cyclolignan and their activity against drug-resistant bacteria

Larrea tridentata antibacterial lignan 4,4′-dihydroxy-3-methoxy-6,7′-cyclolignan (1) was derivatized to obtain eleven new amino ether derivatives (2 A-12 C). The structural elucidation of compounds was performed by analysis of 1D- and 2D NMR spectral data and HRESIMS. The antibacterial activity of compounds was determined against nine drug-resistant bacteria and two strains of Mycobacterium tuberculosis (sensitive ATCC 27294 H37Rv and drug-resistant G122). Results showed that all derivatives were devoid of activity towards six gram-negative clinical isolates assayed. However, seven derivatives displayed antibacterial activity against three gram-positive drug-resistant bacteria. Further, enhancement of antibacterial activity was only observed for the compounds 2 A and 10 C-12 C (MIC of 12.5 µg/mL) which were two-fold more active than the starting material 1 against vancomycin-resistant Enterococcus faecium. All derivatives, except compound 9 B, showed antitubercular activity against both M. tuberculosis strains. Interestingly, all the compounds, except for 2 A and 11 A, were more active than the starting material 1 (MIC of 50 µg/mL). Compound 4 C was the only compound as active as the positive control ethambutol against the drug-resistant strain M. tuberculosis G122 (MIC of 6.25 µg/mL). In addition, the derivative 7 C was the most active compound against the sensitive strain M. tuberculosis H37Rv (MIC of 6.25 µg/mL)     

Design,synthesis and molecular modeling studies of new series of s-triazine derivatives as antimicrobial agents against multi-drug resistant clinical isolates

Three novel series of s-triazine derivatives, including thirty-five new compounds 2a-d, 3a-3p, 4b-d, 5b-d, 6d-6d, and 7a-7f were synthesized comprising a diversity of substituents based on the structure of Astrazeneca arylaminotriazine DNA gyrase B inhibitor. The antimicrobial activity was determined for all compounds against Staphylococcus aureus, Escherichia coli and Candida albicans using the two-fold serial dilution technique and against reference standards Ampicillin for the antibacterial screening and Clotrimazole regarding the antifungal evaluation. The tested compounds showed strong to moderate antibacterial inhibitory action and weak antifungal activity. Compounds 3j and 6b were the most potent antibacterial agents against the tested strains and multi-drug resistant (MDR) clinical isolates of Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA1) with minimal toxicity in comparison to the reference drugs. In silico molecular properties calculations and molecular docking study for 3j and 6b revealed that both compounds could be considered as promising antibacterial DNA gyrase B inhibitors.     

Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial agents effective against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA)

Occurrence of infections due to the drug resistant Staphylococcus aureus is on rise necessitating the need for rapid development of new antibacterial agents. In our present work, a series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A. baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125–8 µg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC₅₀ = >10–>100 µg/mL) and exhibited favourable selectivity index (SI = 40–>200). The compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus including VRSA. The promising results obtained indicated the potential use of the above series of compounds as promising antibacterial agents for the treatment of multidrug resistant Staphylococcus aureus infections.     

Design,synthesis and antiplasmodial activity of novel imidazole derivatives based on 7-chloro-4-aminoquinoline

A series of short chain 4-aminoquinoline-imidazole derivatives have been synthesized in one pot two step multicomponent reaction using van leusen standard protocol. The diethylamine function of chloroquine is replaced by substituted imidazole derivatives containing tertiary terminal nitrogen. All the synthesized compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (K1) strains of Plasmodium falciparum. Some of the compounds (6, 8, 9 and 17) in the series exhibited comparable activity to CQ against K1 strain of P. falciparum. All the compounds displayed resistance factor between 0.09 and 4.57 as against 51 for CQ. Further, these analogues were found to form a strong complex with hematin and inhibit the β-hematin formation, therefore these compounds act via heme polymerization target.     

Enhancing activity of antibiotics against Staphylococcus aureus: Zanthoxylum capense constituents and derivatives

Six compounds (1–6), isolated from the methanol extract of the roots of the African medicinal plant Zanthoxylum capense Thunb. (Rutaceae), and seven ester derivatives (7–13) were evaluated for their antibacterial activities and modulatory effects on the MIC of antibiotics (erythromycin, oxacillin, and tetracycline) and ethidium bromide (EtBr) against a Staphylococcus aureus reference strain (ATCC 6538). Using the same model, compounds 1–13 were also assessed for their potential as efflux pump inhibitors by a fluorometric assay that measures the accumulation of the broad range efflux pump substrate EtBr. Compounds 8 and 11 were further evaluated for their antibacterial, modulatory and EtBr accumulation effects against four additional S. aureus strains, which included two clinical methicillin-resistant S. aureus (MRSA) strains. Compounds (1–13) have not shown antibacterial activity at the concentration ranges tested. When evaluated against S. aureus ATCC 6538, oxychelerythrine (1) a benzophenanthridine alkaloid, showed the highest modulatory activity enhancing the susceptibility of this strain to all the tested antibiotics from two to four-fold. Ailanthoidiol diacetate (8) and ailanthoidiol di-2-ethylbutanoate (11) were also good modulators when combined with EtBr, increasing the bacteria susceptibility by four and two-fold, respectively. In the EtBr accumulation assay, using ATCC 6538 strain, the phenylpropanoid (+)-ailanthoidiol (6) and most of its ester derivatives (8−11) exhibited higher activity than the positive control verapamil. The highest effects were found for compounds 8 and 11 that also increased the accumulation of EtBr, using S. aureus ATCC 25923 as model. Furthermore, both compounds (8, 11) were able to enhance the ciprofloxacin activity against the MRSA clinical strains tested, causing a reduction of the antibiotic MIC values from two to four-fold. The EtBr accumulation assay revealed that this modulation activity was not due to an inhibition of efflux pumps mechanism.These results suggested that Z. capense constituents may be valuable as leads for restoring antibiotic activity against MRSA strains.     

Synthesis and antibacterial activity of novel 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives

A novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. These derivatives were found to have strong activity against susceptible and resistant bacteria strains. Among them, compounds 7a and 7q showed the most potent activity (0.125?µg/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4?µg/mL) against penicillin-resistant S. aureus ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved activity (8?µg/mL) against erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited potent and balanced activity against the tested drug-susceptible and -resistant bacterial strains.     

A novel series of 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing 1,2,3-triazole group: Design,synthesis and antibacterial evaluation

A series of novel 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing the 1,2,3-triazole group were designed, synthesized, and evaluated for their in vitro antibacterial activity. The antibacterial results indicated that most of the target compounds not only increased their activity against resistant bacterial strains, but also partially retained the activity against sensitive bacterial strains compared with clarithromycin. Among them, 13d had the best antibacterial activity against resistant strains, including Streptococcus pneumoniae B1 expressing the ermB gene (16 µg/mL), Streptococcus pneumoniae AB11 expressing the mefA and ermB genes (16 µg/mL) and Streptococcus pyogenes R1 (16 µg/mL), showing >16, 8 and 16-fold higher activity than that of CAM, respectively. Moreover, 13d and 13g exhibited the best antibacterial activity against sensitive bacterial strains, including Staphylococcus aureus ATCC25923 (4 µg/mL) and Bacillus Subtilis ATCC9372 (1 µg/mL). The MBC results showed that the most promising compounds 13d and 13g exhibited antibacterial activity through bacteriostatic mechanism, while the time-kill kinetic experiment revealed bactericidal kinetics of 13g from microscopic point of view. In vitro antibacterial experiments and molecular docking results further confirmed that it was feasible to our initial design strategy by modifying the C-3 and C-11 positions of clarithromycin to increase the activity against resistant bacteria.     

6-Bromoindolglyoxylamido derivatives as antimicrobial agents and antibiotic enhancers

The combination of increased incidence of drug-resistant strains of bacteria and a lack of novel drugs in development creates an urgency for the search for new antimicrobials. Initial screening of compounds from an in-house library identified two 6-bromoindolglyoxylamide polyamine derivatives (3 and 4) that exhibited intrinsic antimicrobial activity towards Gram-positive bacteria, Staphylococcus aureus and S. intermedius with polyamine 3 also displaying in vitro antibiotic enhancing properties against the resistant Gram-negative bacterium Pseudomonas aeruginosa. A series of 6-bromo derivatives (5–15) were prepared and biologically evaluated, identifying analogues with enhanced antibacterial activity towards Escherichia coli and with moderate to excellent antifungal properties. Polyamine 3, which includes a spermine chain, was the most potent of the series – its mechanism of action was attributed to rapid membrane permeabilization and depolarization in both Gram-positive and Gram-negative bacteria.     

Synthesis,identification and in vitro biological evaluation of some novel quinoline incorporated 1,3-thiazinan-4-one derivatives

The present study describes the synthesis of two new series of 3-hydroxy-N-(4-oxo-2-phenyl-1,3-thiazinan-3-yl)-8-(trifluoromethyl)quinoline-2-carboxamide derivatives (4a–j) and 3-((7-chloroquinolin-4-ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one derivatives (5a–7j). All the compounds were synthesized in moderate to good yield by one-pot three component cyclo-condensation reaction. The newly synthesized compounds were characterized by FT-IR, ¹H, ¹³C NMR and elemental analysis. The compounds were screened for their in vitro antibacterial activity against a panel of pathogenic bacterial strains, antitubercular activity against Mycobacterium tuberculosis H₃₇Rv and also for their in vitro antimalarial activity against Plasmodium falciparum. Among the synthesized compounds two of them (4f and 5f) showed excellent antibacterial activity against C. tetani at 15.6 μg/mL. Some of them exhibited excellent antitubercular (4f & 5f) and good antimalarial (4f, 5f & 6f) activity compared with the first line drugs.     

Antibacterial activity of singly and doubly modified salinomycin derivatives

The increasing challenge of antibiotic resistance stimulates the search for novel antibacterial agents, especially such that would be effective against multi-drug resistant bacterial strains. Fortunately, natural compounds are excellent sources of potentially new drug leads. Particularly interesting in this context are polyether antibiotic salinomycin (SAL) and its semi-synthetic derivatives, as they exhibit large spectrum of bioactivity. We synthesized and evaluated the antibacterial activity of a series of SAL analogs; four singly (2–3, 15, 17) and two doubly modified (16, 18) derivatives were found to show excellent inhibitory activity not only against planktonic Gram(+) bacterial cells, but also towards select strains of methicillin-resistant staphylococci with the MIC values of 1–4 µg mL⁻¹. Of note, the most promising candidates were more effective in preventing bacterial biofilm formation than unmodified SAL and a commonly used antibiotic – ciprofloxacin. Furthermore, we proved that rational modification of C20 hydroxyl of SAL may reduce genotoxic properties of the obtained analogs. Mechanistically, the structure-activity relationship studies suggested that electroneutral transport mechanism could be beneficial in terms of ensuring high antibacterial activity of SAL derivatives.     

Synthesis and biological evaluation of rhodanine derivatives bearing a quinoline moiety as potent antimicrobial agents

Three series of rhodanine derivatives bearing a quinoline moiety (6a–h, 7a–g, and 8a–e) have been synthesized, characterized, and evaluated as antibacterial agents. The majority of these compounds showed potent antibacterial activities against several different strains of Gram-positive bacteria, including multidrug-resistant clinical isolates. Of the compounds tested, 6g and 8c were identified as the most effective with minimum inhibitory concentration (MIC) values of 1 μg/mL against multidrug-resistant Gram-positive organisms, including methicillin-resistant and quinolone-resistant Staphylococcus aureus (MRSA and QRSA, respectively). None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL. The cytotoxic activity assay showed that compounds 6g, 7g and 8e exhibited in vitro antibacterial activity at non-cytotoxic concentrations. Thus, these studies suggest that rhodanine derivatives bearing a quinoline moiety are interesting scaffolds for the development of novel Gram-positive antibacterial agents.     

Synthesis and evaluation of the antibacterial activities of aryl substituted dihydrotriazine derivatives

Five series of dihydrotriazine derivatives containing chalcone (13a–i), phenoxy acetophenone (14a–b), benzyl benzene (15a–c), naphthoxyl acetophenone (16a–b) and benzyl naphthalene (17a–h) moieties were designed and synthesized. The antibacterial and antifungal activities of these compounds were evaluated against several strains of Gram-positive and Gram-negative bacteria, as well as a single fungus. Compound 17h was found to be the most potent of all of the compounds tested, with an MIC value of 0.5?μg/mL against several Gram-positive (Staphylococcus aureus 4220 and QRSA CCARM 3505) and Gram-negative (Escherichia coli 1924) strains of bacteria. However, this compound was inactive against Pseudomonas aeruginosa 2742 and Salmonella typhimurium 2421, indicating that its antibacterial spectrum is similar to those of the positive controls gatifloxacin and moxifloxacin. The cytotoxic activity of the compound 13i, 16b and 17h was assessed in Human normal liver cells.     

Design,synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1–6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4–6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.     

Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine

A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7?l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06–2?μg/mL) and three resistant strains (0.25–4?μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16?μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.     

Design and synthesis of positional isomers of 5 and 6-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles as possible antimicrobial and antitubercular agents

In this Letter, we report the structure–activity relationship (SAR) studies on series of positional isomers of 5(6)-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles derivatives 7(a–j) and 8(a–j) synthesized in good yields and characterized by ¹H NMR, ¹³C NMR and mass spectral analyses. The crystal structure of 7a was evidenced by X-ray diffraction study. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, (Gram-positive), Escherichia coli and Klebsiella pneumoniae (Gram-negative), antifungal activity against Candida albicans, Aspergillus flavus and Rhizopus sp. and antitubercular activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis, Mycobacterium fortuitum and MDR-TB strains. The synthesized compounds displayed interesting antimicrobial activity. The compounds 7b, 7e and 7h displayed significant activity against Mycobacterium tuberculosis H37Rv strain.     

Metal-based biologically active azoles and β-lactams derived from sulfa drugs

Metal complexes of Schiff bases derived from sulfamethoxazole (SMZ) and sulfathiazole (STZ), converted to their β-lactam derivatives have been synthesized and experimentally characterized by elemental analysis, spectral (IR, ¹H NMR, ¹³C NMR, and EI-mass), molar conductance measurements and thermal analysis techniques. The structural and electronic properties of the studied molecules were investigated theoretically by performing density functional theory (DFT) to access reliable results to the experimental values. The spectral and thermal analysis reveals that the Schiff bases act as bidentate ligands via the coordination of azomethine nitrogen to metal ions as well as the proton displacement from the phenolic group through the metal ions; therefore, Cu complexes can attain the square planner arrangement and Zn complexes have a distorted tetrahedral structure. The thermogravimetric (TG/DTG) analyses confirm high stability for all complexes followed by thermal decomposition in different steps. In addition, the antibacterial activities of synthesized compounds have been screened in vitro against various pathogenic bacterial species. Inspection of the results revealed that all newly synthesized complexes individually exhibit varying degrees of inhibitory effects on the growth of the tested bacterial species, therefore, they may be considered as drug candidates for bacterial pathogens. The free Schiff base ligands (1–2) exhibited a broad spectrum antibacterial activity against Gram negative Escherichia coli, Pseudomonas aeruginosa, and Proteus spp., and Gram positive Staphylococcus aureus bacterial strains. The results also indicated that the β-lactam derivatives (3–4) have high antibacterial activities on Gram positive bacteria as well as the metal complexes (5–8), particularly Zn complexes, have a significant activity against all Gram negative bacterial strains. It has been shown that the metal complexes have significantly higher activity than corresponding ligands due to chelation process which reduces the polarity of metal ion by coordinating with ligands.     

Novel 4-N-substituted aryl but-3-ene-1,2-dione derivatives of piperazinyloxazolidinones as antibacterial agents

Novel (5S)-N-[3-(3-fluoro-4-{4-[2-oxo-4-(substituted aryl)-but-3-enoyl]-piperazin-1-yl}-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 3a–j analogues were synthesized and their in vitro antibacterial activity was evaluated. Most of the compounds of series showed superior in vitro activity against Gram-positive resistant strains than linezolid. Compound 3f is the most potent compound in the series with 0.04–0.39 μg/mL MIC.     

Synthesis and antibacterial activity of novel phosphonium salts on the basis of pyridoxine

A series of 13 phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties was demonstrated. Among synthesized compounds 5,6-bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (compound 20) was found to be the most effective towards Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 5 μg/ml). The mechanism of antibacterial activity of this compound probably involves cell penetration and interaction with genomic and plasmid DNA.