Synthesis and evaluation of ether and halogenated derivatives of mannopeptimycin glycopeptide antibiotics

A number of 6-O-ether and 4-O-ether derivatives of mannopeptimycin-alpha with different steric bulk and lipophilicity were synthesized for structure-activity relationship study. Novel iodo and bromo mannopeptimycin-alpha were also prepared. These compounds were synthesized via electrophilic aromatic substitution. Many of the new ether derivatives exhibited potent antibacterial activity against Gram-positive resistant strains including VRE, MRSA, and PRSP.     

Synthesis of macrolones with central piperazine ring in the linker and its influence on antibacterial activity

Three macrolides, clarithromycin, azithromycin and 11-O-Me-azithromycin have been selected for the construction of a series of new macrolone derivatives. Quinolone-linker intermediates are prepared by Sonogashira-type C(6)-alkynylation of 6-iodoquinolone precursors. The final macrolones, differing by macrolide moiety and substituents at the position N-1 of the quinolone or by the presence of an ethyl ester or free acid on the quinolone unit attached via a linker. The linker comprises of a central piperazine ring bonded to the 4″-O position of cladinose by 3-carbon ester or ether functionality. Modifications of the linker did not improve antibacterial properties compared to the previously reported macrolone compounds. Linker flexibility seems to play an important role for potency against macrolide resistant respiratory pathogens.     

Synthesis and biological evaluation of novel C (7) modified chrysin analogues as antibacterial agents

The natural product, chrysin (5,7-dihydroxy flavone), obtained from Oroxylum indicum, exhibits numerous biological activities including anticancer, anti-inflammatory, and antiallergic activities. Three series of chrysin analogues were prepared, in which chrysin and heterocyclic moieties are separated by 3-carbon, 4-carbon, and 6-carbon spacers. All the derivatives were screened for antibacterial activity against a panel of susceptible and resistant Gram-positive and Gram-negative organisms. It was observed that most of the derivatives displayed significant activity as compared to their parent compound (chrysin).     

Effect of varying the 4'-position of arbekacin derivatives on antibacterial activity against MRSA and Pseudomonas aeruginosa

4'-Deoxy-4'-episubstituted arbekacin derivatives and 4'-epi-5-deoxy-5-episubstituted arbekacin derivatives were designed and synthesized. Arbekacin and 4'-epiarbekacin both displayed the same antibacterial activity against Staphylococcus aureus (including methicillin-resistant S. aureus (MRSA)) and Pseudomonas aeruginosa. The 4'-epi-5-deoxy-5-episubstituted arbekacin derivatives showed potent antibacterial activity. Among them, the antibacterial activity of 5,4'-diepiarbekacin was superior to that of arbekacin or 5-episubstituted arbekacin against Gram-positive and Gram-negative bacteria. The 6'-N-methyl derivative of the 5,4'-diepiarbekacin was effective against P. aeruginosa expressing an aminoglycoside-modifying enzyme AAC(6')-Ib.     

Synthesis and antibacterial activity of 4'-O-heteroarylcarbamoyl derivatives of macrolide

A series of novel 4'-position modified macrolide derivatives has been synthesized via a facile procedure. Their in vitro antibacterial activities against constitutively erythromycin-resistant strains were evaluated. Among the derivatives tested, compound 8a which has 11,12-carbamate and 4'-O-heteroarylcarbamoyl groups was found to have potent activity against most resistant bacteria.     

Antibacterial activity of 3-methylbenzo[d]thiazol-methylquinolinium derivatives and study of their action mechanism

The increasing incidence of multidrug resistant bacterial infection renders an urgent need for the development of new antibiotics. To develop small molecules disturbing FtsZ activity has been recognized as promising approach to search for antibacterial of high potency systematically. Herein, a series of novel quinolinium derivatives were synthesized and their antibacterial activities were investigated. The compounds show strong antibacterial activities against different bacteria strains including MRSA, VRE and NDM-1 Escherichia coli. Among these derivatives, a compound bearing a 4-fluorophenyl group (A2) exhibited a superior antibacterial activity and its MICs to the drug-resistant strains are found lower than those of methicillin and vancomycin. The biological results suggest that these quinolinium derivatives can disrupt the GTPase activity and dynamic assembly of FtsZ, and thus inhibit bacterial cell division and then cause bacterial cell death. These compounds deserve further evaluation for the development of new antibacterial agents targeting FtsZ.     

Synthesis and antimicrobial activity of erythromycin-A oxime analogs

A series of erythromycin-A oxime ether as well as esters have been synthesized. Ether derivatives were synthesized through the epoxy ether intermediate of erythromycin-9-oxime, followed by opening of the epoxy linkage through various amines, whereas esters have been prepared through DCC mediated protocol. These derivatives have been evaluated for antibacterial activity and found to be as active as erythromycin-A.     

Synthesis,crystal and antibacterial studies of diversely functionalized tetrahydropyridin-4-ol

In an effort to expand the spectrum of antibacterial activity associated with piperidin-4-one derivatives, we have synthesized two series of 3-carboxyethyl-2,6-diphenyl-4-hydroxy-Δ³-tetrahydropyridine derivatives bearing diversified heterocyclic and aromatic systems at the nitrogen atom through acetyl (6–18) and 2-propanoyl (9–31) linkers. Unlike acetyl derivatives, NMR spectral pattern of the propanoyl counterparts revealed the existence of pair of rotational isomers (syn and anti) in solution at room temperature due to the hindered rotation about N–CO bond. X-ray crystal studies of 9 and 24 clearly pointed out that all the compounds existed in only one form particularly, in stable syn form in solid state. Each of the compounds was screened for their in vitro antibacterial activity against nine human pathogenic Gram-positive strains including multiple drug resistant organisms and seven problematic Gram-negative strains. Among the various heterocycles examined here, imidazole substituted derivatives 12 and 25 exhibited antibacterial activity approaching that of Linezolid and Trovafloxacin drugs particularly against multiple resistant Enterococcus faecium-VanA phenotype strains.     

6-Alkylquinolone-3-carboxylic acid tethered to macrolides synthesis and antimicrobial profile

Two series of clarithromycin and azithromycin derivatives with terminal 6-alkylquinolone-3-carboxylic unit with central ether bond in the linker were prepared and tested for antimicrobial activity. Quinolone-linker intermediates were prepared by Sonogashira-type C(6)-alkynylation of 6-iodo-quinolone precursors. In the last step, 4″ site-selective acylation of 2′-protected macrolides was completed with the EDC reagent, which selectively activated a terminal, aliphatic carboxylic group in dicarboxylic intermediates. Antimicrobial activity of the new series of macrolones is discussed. The most potent compound, 4″-O-{6-[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydroquinolin-6-yl)-propoxy]-hexanoyl}-azithromycin (10), is highly active against bacterial respiratory pathogens resistant to macrolide antibiotics and represents a promising lead for further investigation.     

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.     

Diphenyl ether and benzophenone derivatives from the marine mangrove-derived fungus Penicillium sp. MA-37

Further investigation of the marine mangrove-derived fungal strain Penicillium sp. MA-37 led to the isolation of one new benzophenone, iso-monodictyphenone (1), two new diphenyl ether derivatives penikellides A (2) and B (3), and two known analogs monodictyphenone (4) and 6-[2-hydroxy-6-(hydroxymethyl)-4-methylphenoxy]-2-methoxy-3-(1-methoxy-3-methylbutyl)benzoic acid (5). The structures of these compounds were elucidated by spectroscopic analyses including 1D- and 2D-NMR and mass spectrometry. The brine shrimp lethality and antibacterial activity against five aquaculture pathogens were evaluated.     

Synthesis and in vitro study of novel 7-O-acyl derivatives of Oroxylin A as antibacterial agents

A series of Oroxylin A derivatives, prepared by alkylation and condensation, were fully characterized by spectroscopic methods. All the derivatives were screened for antibacterial activity against a panel of susceptible and resistant Gram-positive and Gram-negative organisms. It was observed that acylation of 7-OH group in Oroxylin A significantly enhanced the activity as compared to their parent compound (Oroxylin A).     

Naphthalene Derivatives and Quinones from Ventilago denticulata and Their Nitric Oxide Radical Scavenging,Antioxidant, Cytotoxic,Antibacterial, and Phosphodiesterase Inhibitory Activities

New naphthalene derivatives ( 1 and 2 ) and a new isomer ( 3 ) of ventilagolin, together with known anthraquinones, chrysophanol ( 4 ), physcion or emodin 3‐methyl ether ( 5 ), and emodin ( 6 ), were isolated from vines of Ventilago denticulata. The isolated compounds exhibited cytotoxic activity with IC₅₀ values of 1.15 – 40.54 μg/ml. Compounds 1 – 3 selectively exhibited weak antibacterial activity (MIC values of 200.0 – 400.0 μg/ml), while emodin ( 6 ) displayed moderate antibacterial activity with MIC value of 25.0 μg/ml. The isolated compounds showed nitric oxide and DPPH radical scavenging activities. Compounds 1 – 3 and 6 exhibited weak xanthine oxidase inhibitory activity, while emodin ( 6 ) acted as an aromatase inhibitor with the IC₅₀ value of 10.1 μm . Compounds 1 and 2 exhibited phosphodiesterase 5 inhibitory activity with IC₅₀ values of 8.28 μm and 6.48 μm , respectively.     

Synthesis and potent antimicrobial activity of some novel methyl or ethyl 1H-benzimidazole-5-carboxylates derivatives carrying amide or amidine groups

A series of benzimidazole-5-carboxylic acid alkyl ester derivatives carrying amide or amidine substituted methyl or phenyl groups at the position C-2 were synthesised and evaluated for antibacterial and antifungal activities against S. aureus, methicillin resistant S. aureus (MRSA), S. faecalis, methicillin resistant S. epidermidis (MRSE), E. coli and C. albicans. The results showed that while all simple acetamides are essentially inactive, aromatic amides and amidines have potent antibacterial activities. Aromatic amidine derivatives 13 f-h exhibited the best inhibitory activity with 1.56-0.39 microg/mL MIC values against MRSA and MRSE.     

Design,Microwave‐Assisted Synthesis and in Vitro Antibacterial and Antifungal Activity of 2,5‐Disubstituted Benzimidazole

Seventeen novel 2,5‐disubstituted benzimidazole derivatives were designed, synthesized and evaluated for their antibacterial activities. The tested compounds B1 – B4 and C2 – C6 exhibited not only good antifungal activity but also favorable broad‐spectrum antibacterial activity. Also, the lowest MIC of antibacterial and antifungal activity was 2 μg/mL and 4 μg/mL, respectively. It suggested that the structure of compound including the different substituent and its sites directly affected the efficacy of the synthesized compounds.     

Synthesis of plaunotol derivatives and their antibacterial activities against Helicobacter pylori.

Plaunotol, a known antiulcer drug, has antibacterial activities against Helicobacter pylori. Plaunotol thiourea derivatives 2--4 and diol derivatives 6--10 were designed in search for a compound with high antibacterial activities. Thiourea derivatives 2--4 were synthesized regioselectively using our effective synthetic route for plaunotol (1), and diol derivatives 6--10 were also synthesized. Their antibacterial activities against H. pylori are described and we found that the most potent antibacterial agent was C1-thiourea derivative 2c.     

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)     

Synthesis and biological activity of [Leu5]enkephalin derivatives containing D-glucose

The synthesis of some [Leu5]enkephalin derivatives is described in which D-glucose has been linked to the opioid pentapeptide through the ester bond involving the carboxyl function at the C-terminal with C-1 or C-6 of the D-glucopyranose moiety. Enkephalin derivatives were assayed for opioid activity and found to be full agonists in bioassays based on inhibition of electrically evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD). The obtained results suggest that the opioid activity of the tested glucoconjugates depend upon the ester bond position in the molecule. Whereas 1-O conjugate 5 was somewhat more potent than [Leu5]enkephalin in the GPI assay, the 6-O conjugates, with the exception of 1-O-benzyl derivative 11, were considerably less potent. All enkephalin derivatives were delta-receptor selective; in particular, the acetylated analog 8 was three times more delta-receptor selective than [Leu5]enkephalin.     

New derivatives of 11-methyl-6-[2-(dimethylamino)ethyl]-6H-indolo[2,3-b]quinoline as cytotoxic DNA topoisomerase II inhibitors

Novel indolo[2,3-b]quinoline derivatives substituted at N-6 and C-2 or C-9 positions with (dimethylamino)ethyl chains linked to heteroaromatic core by ether, amide or amine bonds, were manufactured and evaluated in vitro for their cytotoxic activity against several cell lines of different origin including multidrug resistant sublines and tested for their ability to influence the cell cycle and inhibit topoisomerase II activity. It was found, that all compounds show cytotoxic activity against cell lines tested, including multidrug resistant LoVo/DX, MES-SA/DX5 and HL-60 sublines. The tested compounds induce the G(2)M phase cell cycle arrest in Jurkat cells, and inhibit topoisomerase II activity.     

Synthesis and structure–activity relationship of a novel class of 15-membered macrolide antibiotics known as ‘11a-azalides’

Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An efficient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based on this methodology, novel 15-membered macrolides, known as ‘11a-azalides’, with substituents at the C12, C13, or C4″ positions were synthesized and their antibacterial activities were evaluated. These derivatives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae. Among them, the C4″ substituted derivatives had the most potent activity against erythromycin-resistant S. pneumoniae.