Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides

A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5 μg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125–1 μg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372.     

Synthesis,molecular docking and biological evaluation of metronidazole derivatives containing piperazine skeleton as potential antibacterial agents

Metronidazole has a broad-spectrum antibacterial activity. Hereby a series of novel metronidazole derivatives were designed and synthesized based on nitroimidazole scaffold in order to find some more potent antibacterial drugs. For these compounds which were reported for the first time, their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4m represented the most potent antibacterial activity against S. aureus ATCC 25923 with MIC of 0.003 μg/mL and it showed the most potent activity against S. aureus TyrRS with IC₅₀ of 0.0024 μM. Molecular docking of 4m into S. aureus tyrosyl-tRNA synthetase active site were also performed to determine the probable binding mode.     

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 and antibacterial activity of novel 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs

Three novel structural series of 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs were designed, synthesized and evaluated for their in vitro antibacterial activity. All the target compounds exhibited excellent activity against erythromycin-susceptible Streptococcus pyogenes, and significantly improved activity against three phenotypes of erythromycin-resistant Streptococcus pneumoniae compared with clarithromycin and azithromycin. Among the three series of azithromycin analogs, the novel series of 11,4″-disubstituted azithromycin analogs 9a–k exhibited the most effective and balanced activity against susceptible and resistant bacteria. Among them, compound 9j showed the most potent activity against Staphylococcus aureus ATCC25923 (0.008 µg/mL) and Streptococcus pyogenes R2 (1 µg/mL). Besides, all the 11,4″-disubstituted azithromycin analogs 9a–k except 9f shared the identical activity with the MIC value <0.002 µg/mL against Streptococcus pyogenes S2. Furthermore, compounds 9g, 9h, 9j and 9k displayed significantly improved activity compared with the references against all the three phenotypes of resistant S. pneumoniae. Particularly, compound 9k was the most effective (0.06, 0.03 and 0.125 µg/mL) against all the erythromycin-resistant S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, exhibiting 2133, 133 and 2048-fold more potent activity than azithromycin, respectively.     

Design,synthesis and biological activity evaluation of novel 2,6-difluorobenzamide derivatives through FtsZ inhibition

Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram-negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25–1 μg/mL, and good activity (MIC < 10 μg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1 μg/mL against Bacillus subtilis and Staphylococcus aureus.     

Syntheses of benzophenone-xanthone hybrid polyketides and their antibacterial activities

Muchimangins are benzophenone-xanthone hybrid polyketides produced by Securidaca longepedunculata. However, their biological activities have not been fully investigated, since they are minor constituents in this plant. To evaluate the possibility of muchimangins as antibacterial agent candidates, five muchimangin analogs were synthesized from 2,4,5-trimethoxydiphenyl methanol and the corresponding xanthones, by utilizing p-toluenesulfonic acid monohydrate for the Brønsted acid-catalysis. The antibacterial assays against Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and Gram-negative bacteria, Klebsiella pneumoniae and Escherichia coli, revealed that the muchimangin analogs (±)-1,3,6,8-tetrahydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (1), (±)-1,3,6-trihydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (2), and (±)-1,3-dihydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (3) showed significant activities against S. aureus, with MIC values of 10.0, 10.0, and 25.0 μM, respectively. Analogs (±)-1 and (±)-2 also exhibited antibacterial activities against B. subtilis, with MIC values of 50.0 and 12.5 μM, respectively. Furthermore, (+)-3 enhanced the antibacterial activity against S. aureus, with a MIC value of 10 μM.     

Antibacterial activity of an epoxidised prenylated cinnamaldehdye derivative from Vepris glomerata

A prenylated cinnamaldehyde (glomeral), together with the known p-hydroxycinnamic acid, caffeic acid, methyl cinnamate, hesperetin, scoparone, skimmianine, syringaresinol and two limonoids (limonin and limonyl acetate) were isolated from the roots and stem bark of Vepris glomerata. The antibacterial assay of the isolated compounds indicated an inhibition zone, ranging from 8 to 16 mm, against standard strains of Staphylococcus aureus (ATCC 29213, 25923) and Shigella dysentrieae. Glomeral inhibited the growth of S. aureus and S. dysentrieae at low concentrations (MIC of 2 μg/mL and 0.4 μg/mL respectively). Of the other compounds tested, hesperetin displayed good antibacterial activity, the limonoids, scoparone and skimmianine displayed moderate antibacterial activity and the cinnamic acid derivatives were inactive against the test pathogens. This study provides a rationale for the use of V. glomerata in its treatment of bacterial infections.     

Neolignans from Callistemon lanceolatus

Two neolignans, named callislignan A and B together with known C-methyl-flavonoids, a lignan and pentacyclic triterpenoid esters were isolated from the leaves of Callistemon lanceolatus. Their structures were characterized by spectroscopic methods. Callislignan A and B had antibacterial activity against Staphylococcus aureus ATCC25923 and MRSA SK1 with callislignan B having an MIC of 8 μg/mL.     

Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC₉₀ = 0.125 μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC₅₀ of 85.9 μM and a favorable profile in the anesthetized guinea pig model.     

Synthesis and antibacterial activity of 5-methylphenanthridium derivatives as FtsZ inhibitors

5-Methylphenanthridium derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative bacteria. Among them, compounds 5A2, 5B1, 5B2, 5B3, 5C1 and 5C2 displayed the best on-target antibacterial activity with an MIC value of 4 µg/mL against B. subtilis ATCC9372 and S. pyogenes PS, showing over 2-fold better activity than sanguinarine. The SARs showed that the 5-methylphenanthridium derivatives with the alkyl side chains at the 2-postion, especially the straight alkyl side chains exerted better on-target antibacterial activity.     

Antimicrobial lignans derived from the roots of Streblus asper

Four new lignans, (7′R,8′S)-4,4'-Dimethoxy-strebluslignanol (1), 3'-Hydroxy-isostrebluslignaldehyde (2), 3,3'-Methylene-bis(4-hydroxybenzaldehyde) (3), and 4-Methoxy-isomagnaldehyde (4), and six known lignans (5–10), were isolated from the roots of Streblus asper. The structures of these molecules were elucidated through various spectroscopic methods of analysis, including 1D and 2D NMR. The stereochemistry at the chiral centres was determined using the CD spectrum and from coupling constant and optical rotation data. Compounds 1–6 showed good antimicrobial activity against Saccharomyces cerevisiae (ATCC 9763), Bacillus subtilis (ATCC 6633), Pseudomonas aeruginosa (ATCC 9027), Escherichia coli (ATCC 11775), and Staphylococcus aureus (ATCC 25923), with MIC values ranging from 0.0150 to 0.0940 μM.     

Bis-phosphonium salts of pyridoxine: The relationship between structure and antibacterial activity

A series of 23 novel bis-phosphonium salts based on pyridoxine were synthesized and their antibacterial activities were evaluated in vitro. All compounds were inactive against gram-negative bacteria and exhibited the structure-dependent activity against gram-positive bacteria. The antibacterial activity enhanced with the increase in chain length at acetal carbon atom in the order n-Pr > Et > Me. Further increasing of length and branching of alkyl chain leads to the reduction of antibacterial activity. Replacement of the phenyl substituents at the phosphorus atoms in 5,6-bis(triphenylphosphonio(methyl))-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine dichloride (compound 1) with n-butyl, m-tolyl or p-tolyl as well as chloride anions in the compound 1 with bromides (compound 14a) increased the activity against Staphylococcus aureus and Staphylococcus epidermidis up to 5 times (MICs = 1–1.25 μg/ml). But in practically all cases chemical modifications of compound 1 led to the increase of its toxicity for HEK-293 cells. The only exception is compound 5,6-bis[tributylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (10a) which demonstrated lower MIC values against S. aureus and S. epidermidis (1 μg/ml) and lower cytotoxicity on HEK-293 cells (CC₅₀ = 200 μg/ml). Compound 10a had no significant mutagenic and genotoxic effects and was selected for further evaluation. It should be noted that all bis-phosphonium salt based on pyridoxine were much more toxic than vancomycin.     

Efficient synthesis and antimicrobial activity of some novel S-β-d-glucosides of 5-aryl-1,2,4-triazole-3-thiones derivatives

A series of 3-S-β-d-glucosides-4-arylideneamino-5-aryl-1,2,4-triazoles were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,2,4-triazole, Schiff base and glucosides. The structures of the target compounds have been characterized by ¹H NMR, ¹³C NMR, IR, MS and HRMS. All the newly synthesized compounds have been evaluated for their antimicrobial activities in vitro against Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8099) as well as Monilia albican (ATCC 10231). The bioactive assay showed that most of the tested compounds displayed variable inhibitory effects on the growth of the Gram-positive bacterial strain (Staphylococcus aureus), Gram-negative bacterial strains (Escherichia coli) and fungal strains (Monilia albican). All the target compounds exhibited better antifungal activity than antibacterial activity. Especially, compounds 6b, 6c, 6f, 6j, 6k and 6l showed excellent activity against fungus Monilia albican with MIC values of 16 μg/mL.     

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 of fluorinated carbazoles via C–H arylation catalyzed by Pd/Cu bimetal system and their antibacterial activities

An effective intramolecular C–H arylation reaction catalyzed by a bimetallic catalytic system Pd(OAc)₂/CuI for the synthesis of fluorine-substituted carbazoles from corresponding N-phenyl-2-haloaniline derivatives under ligand free conditions is demonstrated. The established method is effective for both N-phenyl-2-bromoaniline and N-phenyl-2-chloroaniline, and requires the low loading of Pd(OAc)₂ (0.5 mol %). A series of new fluorinated carbazoles were synthesized in excellent yields using the protocol (>83%, 19 examples) and were fully characterized by ¹H, ¹³C and ¹⁹F NMR spectral data, HRMS and elemental analysis. All compounds were evaluated for their antibacterial activities against four bacteria (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and methicillin-resistant S. aureus with resistance to gentamicin) by serial dilution technique. All tested compounds showed antibacterial activity against three test strains (S. aureus, B. subtilis and MRSA), and most of these compounds displayed pronounced antimicrobial activities against these three strains with low MIC values ranging from 0.39 to 6.25 μg/mL. Among them, compounds 7 and 14 exhibited potent inhibitory activity better than reference drugs meropenem and streptomycin. Three compounds (2, 4 and 5) showed antibacterial activity against E. coli. with MIC values from 12.5 to 25 μg/mL.     

Antileishmanial evaluation of clubbed bis(indolyl)-pyridine derivatives: One-pot synthesis,in vitro biological evaluations and in silico ADME prediction

A new series of bis(indolyl)-pyridine derivatives 6(a–m) were synthesized by Chichibabin reaction process and evaluated for antileishmanial and antibacterial activities to establish structure–activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, and ammonium acetate in the presence of camphor-10-sulfonic acid as a catalyst. The compounds 6d (IC₅₀ = 102.47 μM) and 6f (IC₅₀ = 99.49 μM) had shown promising antileishmanial against L. donovani promastigotes when compared with standard sodium stibogluconate (IC₅₀ = 490.00 μM). All the synthesized compounds (MIC range = 41.35–228.69 μg/mL) had shown potent antibacterial activity than standard ampicillin (MIC range = 100.00–250.00 μg/mL) against all the tested bacterial strains. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives.     

Diaminopimelic acid (DAP) analogs bearing isoxazoline moiety as selective inhibitors against meso-diaminopimelate dehydrogenase (m-Ddh) from Porphyromonas gingivalis

Two diastereomeric analogs (1 and 2) of diaminopimelic acid (DAP) bearing an isoxazoline moiety were synthesized and evaluated for their inhibitory activities against meso-diaminopimelate dehydrogenase (m-Ddh) from the periodontal pathogen, Porphyromonas gingivalis. Compound 2 showed promising inhibitory activity against m-Ddh with an IC₅₀ value of 14.9 µM at pH 7.8. The two compounds were further tested for their antibacterial activities against a panel of periodontal pathogens, and compound 2 was shown to be selectively potent to P. gingivalis strains W83 and ATCC 33277 with minimum inhibitory concentration (MIC) values of 773 µM and 1.875 mM, respectively. Molecular modeling studies revealed that the inversion of chirality at the C-5 position of these compounds was the primary reason for their different biological profiles. Based on these preliminary results, we believe that compound 2 has properties consistent with it being a lead compound for developing novel pathogen selective antibiotics to treat periodontal diseases.     

Antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2H-chromene and coumarin scaffold

This study reports the synthesis of new 2H-chromene or coumarin based acylhydrazones, which were evaluated for their in vitro antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and compared to the first-line antituberculosis drugs, isoniazid (INH) and ethambutol (EMB). The most active compounds 7m (MIC 0.13 μM), 7o (MIC 0.15 μM) and 7k (MIC 0.17 μM) demonstrated antimycobacterial activity at submicromolar concentration level and remarkably minimal associated cytotoxicity in the human embryonic kidney cell line HEK-293T. Structure-activity relationship for this class of compounds has been established.     

Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group

Conjugation of the NorA substrate berberine and the NorA inhibitor 5-nitro-2-phenyl-1H-indole via a methylene ether linking group gave the 13-substituted berberine-NorA inhibitor hybrid, 3. A series of simpler arylmethyl ether hybrid structures were also synthesized. The hybrid 3 showed excellent antibacterial activity (MIC Staphylococcus aureus, 1.7 μM), which was over 382-fold more active than the parent antibacterial berberine, against this bacterium. This compound was also shown to block the NorA efflux pump in S. aureus.     

Synthesis,molecular docking and biological evaluation of coumarin derivatives containing piperazine skeleton as potential antibacterial agents

A series of 4-hydroxycoumarin derivatives were designed and synthesized in order to find some more potent antibacterial drugs. Their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4g represented the most potent antibacterial activity against Bacillus subtilis and S. aureus with MIC of 0.236, 0.355 μg/mL, respectively. What’s more, it showed the most potent activity against SaFabI with IC₅₀ of 0.57 μM. Molecular docking of 4g into S. aureus Enoyl-ACP-reductase active site were performed to determine the probable binding mode, while the QSAR model was built to check the previous work as well as to introduce new directions.