Geminal dialkyl derivatives of N-substituted pantothenamides: synthesis and antibacterial activity

As a key precursor of coenzyme A (CoA) biosynthesis, pantothenic acid has proven to be a useful backbone to elaborate probes of this biosynthetic pathway, study CoA-utilizing systems, and design molecules with antimicrobial activity. The increasing prevalence of bacterial strains resistant to one or more antibiotics has prompted a renewed interest for molecules with a novel mode of antibacterial action such as N-substituted pantothenamides. Although numerous derivatives have been reported, most are varied at the terminal N-substituent, and fewer at the β-alanine moiety. Modifications at the pantoyl portion are limited to the addition of an ω-methyl group. We report a synthetic route to N-substituted pantothenamides with various alkyl substituents replacing the geminal dimethyl groups. Our methodology is also applicable to the synthesis of pantothenic acid, pantetheine and CoA derivatives. Here a small library of new N-substituted pantothenamides was synthesized. Most of these compounds display antibacterial activity against sensitive and resistant Staphylococcus aureus. Interestingly, replacement of the ProR methyl with an allyl group yielded a new N-substituted pantothenamide which is amongst the most potent reported so far.     

Chemical reactivity and antimicrobial activity of N-substituted maleimides

Several N-substituted maleimides containing substituents of varying bulkiness and polarity were synthesised and tested for antimicrobial and cytostatic activity. Neutral maleimides displayed relatively strong antifungal effect minimum inhibitory concentrations (MICs in the 0.5-4 μg ml(-1) range); their antibacterial activity was structure dependent and all were highly cytostatic, with IC(50) values below 0.1 μg ml(-1). Low antimicrobial but high cytostatic activity was noted for basic maleimides containing tertiary aminoalkyl substituents. Chemical reactivity and lipophilicity influenced antibacterial activity of neutral maleimides but had little if any effect on their antifungal and cytostatic action. N-substituted maleimides affected biosynthesis of chitin and β(1,3)glucan, components of the fungal cell wall. The membrane enzyme, β(1,3)glucan synthase has been proposed as a putative primary target of N-ethylmaleimide and some of its analogues in Candida albicans cells.     

Novel piperidinyloxy oxazolidinone antibacterial agents. Diversification of the N-Substituent

Oxazolidinone antibacterial agents, where the morpholino group of linezolid was replaced with an N-substituted piperidinyloxy moiety, were synthesized and shown to be active against a variety of resistant and susceptible Gram-positive organisms. The functionality attached to the piperidine nitrogen was varied extensively to determine the SAR for this series. One of the most potent compounds, 11, showed in vivo efficacy upon subcutaneous administration in a Staphylococcus aureus Smith murine systemic infection.     

苯并异噻唑啉酮类化合物的生物活性研究

对合成的5种苯并异噻唑啉酮类化合物进行了生物活性研究。抑菌试验结果表明,化合物a与化合物b对大肠杆菌最小抑菌浓度为12.5mg/L。对金黄色葡萄球菌都表现出良好的抑菌活性。对亚心形扁藻,蛋白核小球藻,球等鞭金藻,化合物都有抑制其生长的活性,亚心形扁藻耐受性最高,球等鞭金藻的耐受性最低,蛋白核小球藻的耐受性居中。     

Synthesis and antibacterial activity against Clostridium difficile of novel demethylvancomycin derivatives

To explore the structure-activity relationships (SAR) of demethylvancomycin (2) and find more effective new chemical entities than known glycopeptides for the treatment of Clostridium difficile (C. difficile), 17 novel N-substituted (N-arylmethylene or -aliphatic substituents) demethylvancomycin derivatives were prepared. These analogues have been evaluated in vitro for their antibacterial activities against C. difficile and Enterococcus faecium (E. faecium). Compounds 5d, 5h, and 5i with N-arylmethylene substituents, structurally similar to Oritavancin, showed more potent antibacterial activity against C. difficile than vancomycin (1) or demethylvancomycin (2). Meanwhile, compound 5k with an undecyl side chain showed the most potent antibacterial activity against E. faecium (vancomycin-resistant strain).     

Synthesis and antimycobacterial properties of N-substituted 6-amino-5-cyanopyrazine-2-carboxamides

A series of fifteen new compounds related to pyrazinamide (PZA) were synthesized, characterized with analytical data and screened for antimycobacterial, antifungal and antibacterial activity. The series consists of 6-chloro-5-cyanopyrazine-2-carboxamide and N-substituted 6-amino-5-cyanopyrazine-2-carboxamides, derived from the previous by nucleophilic substitution with various non-aromatic amines (alkylamines, cycloalkylamines, heterocyclic amines). Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis equal to pyrazinamide (12.5-25 μg/mL). More importantly, 6-chloro-5-cyanopyrazine-2-carboxamide and 5-cyano-6-(heptylamino)pyrazine-2-carboxamide were active against Mycobacterium kansasii and Mycobacterium avium, which are unsusceptible to PZA. Basic structure-activity relationships are presented. Only weak antifungal and no antibacterial activity was detected.     

Structure and biological properties of first row d-transition metal complexes with N-substituted sulfonamides

Cobalt (II), copper (II), nickel (II) and zinc (II) complexes with 2-hydroxy-1-naphthaldehyde derived N-substituted sulfonamides have been synthesized and the nature of bonding and structure of compounds have been deduced from physical, analytical and spectral (IR, (1)H NMR, (13)C NMR, Mass and electronic) data. An octahedral geometry has been suggested for the complexes. Complexes along with the ligands were assessed for their antibacterial and antifungal activities on different species of pathogenic bacteria and fungi. The results revealed the ligands to possess moderate to significant antibacterial activity which was, in many cases, enhanced on chelation. Similar results were observed for antifungal activity. Brine shrimp bioassay was also carried out for in vitro cytotoxic properties against Artemia salina.     

Substitution of the GalNAc-α-O-Thr¹¹ residue in drosocin with O-linked glyco-peptoid residue: effect on antibacterial activity and conformational change

One of the obvious disadvantages of natural peptides is their liability to proteases. Among the several solutions for this issue, peptoids or oligomers of N-substituted glycine have emerged as a promising tool that may enhance the stability of proteolysis-susceptible natural peptides. We have synthesized the drosocin and its glyco-peptoid analogues linked O-GalNAc at the Thr(11) residue. One of our glyco-peptoid analogues showed an increased antibacterial activity by the modification of the Thr(11) residue with glyco-peptoid. Structure-activity relationship studies revealed that the antibacterial activity by glyco-peptoid drosocin requires three key elements: free hydroxyl group on the carbohydrate moiety, γ-methyl group of the Thr(11) residue derivative and (S)-configuration over (R)-configuration.     

Synthesis,antibacterial and antifungal activities of some carbazole derivatives

A series of N-substituted carbazole derivatives were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Bacillus proteus, Candida albicans and Aspergillus fumigatus by two fold serial dilution technique. Some of the synthesized compounds displayed comparable or even better antibacterial and antifungal activities than reference drugs fluconazole, chloramphenicol and norfloxacin against tested strains.     

Synthesis and antibacterial activity of N-[2-[5-(methylthio)thiophen-2-yl]-2-oxoethyl] and N-[2-[5-(methylthio)thiophen-2-yl]-2-(oxyimino)ethyl]piperazinylquinolone derivatives

A number of N-substituted piperazinylquinolone derivatives were synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative bacteria. Preliminary results indicated that most compounds tested in this study demonstrated comparable or better activity against Staphylococcus aureus and Staphylococcus epidermidis than their parent piperazinylquinolones as reference drugs. Among these derivatives, ciprofloxacin derivative 5a, containing N-[2-[5-(methylthio)thiophen-2-yl]-2-oxoethyl] residue, showed significant improvement of potency against staphylococci, maintaining Gram-negative coverage.     

Structure and biological properties of first row d-transition metal complexes with N-substituted sulfonamides

Cobalt (II), copper (II), nickel (II) and zinc (II) complexes with 2-hydroxy-1-naphthaldehyde derived N-substituted sulfonamides have been synthesized and the nature of bonding and structure of compounds have been deduced from physical, analytical and spectral (IR, ¹H NMR, ¹³C NMR, Mass and electronic) data. An octahedral geometry has been suggested for the complexes. Complexes along with the ligands were assessed for their antibacterial and antifungal activities on different species of pathogenic bacteria and fungi. The results revealed the ligands to possess moderate to significant antibacterial activity which was, in many cases, enhanced on chelation. Similar results were observed for antifungal activity. Brine shrimp bioassay was also carried out for in vitro cytotoxic properties against Artemia salina.     

New indolicidin analogues with potent antibacterial activity.

Indolicidin is a 13-residue antimicrobial peptide amide, ILPWKWPWWPWRR-NH2, isolated from the cytoplasmic granules of bovine neutrophils. Indolicidin is active against a wide range of microorganisms and has also been shown to be haemolytic and cytotoxic towards erythrocytes and human T lymphocytes. The aim of the present paper is two-fold. First, we examine the importance of tryptophan in the antibacterial activity of indolicidin. We prepared five peptide analogues with the format ILPXKXPXXPXRR-NH2 in which Trp-residues 4,6,8,9,11 were replaced in all positions with X = a single non-natural building block; N-substituted glycine residue or nonproteinogenic amino acid. The analogues were tested for antibacterial activity against both Staphylococcus aureus American type culture collection (ATCC) 25923 and Escherichia coli ATCC 25922. We found that tryptophan is not essential in the antibacterial activity of indolicidin, and even more active analogues were obtained by replacing tryptophan with non-natural aromatic amino acids. Using this knowledge, we then investigated a new principle for improving the antibacterial activity of small peptides. Our approach involves changing the hydrophobicity of the peptide by modifying the N-terminus with a hydrophobic non-natural building block. We prepared 22 analogues of indolicidin and [Phe(4,6,8,9,11)] indolicidin, 11 of each, carrying a hydrophobic non-natural building block attached to the N-terminus. Several active antibacterial analogues were identified. Finally, the cytotoxicity of the analogues against sheep erythrocytes was assessed in a haemolytic activity assay. The results presented here suggest that modified analogues of antibacterial peptides, containing non-natural building blocks, are promising lead structures for developing future therapeutics.     

Synthesis,biological evaluation and in silico studies of novel N-substituted phthalazine sulfonamide compounds as potent carbonic anhydrase and acetylcholinesterase inhibitors

The synthesis, characterization and biological evaluation of a series of novel N-substituted phthalazine sulfonamide (5a-l) are disclosed. Phthalazines which are nitrogen-containing heterocyclic compounds are biologically preferential scaffolds, endowed with versatile pharmacological activity, such as anti-inflammatory, cardiotonic vasorelaxant, anticonvulsant, antihypertensive, antibacterial, anti-cancer action. The compounds were investigated for the inhibition against the cytosolic hCA I, II and AChE. Most screened sulfonamides showed high potency in inhibiting hCA II, widely involved in glaucoma, epilepsy, edema, and other pathologies (K_is in the ranging from 6.32 ± 0.06 to 128.93 ± 23.11 nM). hCA I was inhibited with K_is in the range of 6.80 ± 0.10–85.91 ± 7.57 nM, whereas AChE in the range of 60.79 ± 3.51–249.55 ± 7.89 nM. ADME prediction study of the designed N-substituted phthalazine sulfonamides showed that they are not only with carbonic anhydrase and acetylcholinesterase inhibitory activities but also with appropriate pharmacokinetic, physicochemical parameters and drug-likeness properties. Also, in silico docking studies were investigated the binding modes of selected compounds, to hCA I, II, and AChE.     

Synthesis of new 1-alkyl-, 1-benzyl-, and 1-aryloxyethyl-substituted 4,5-dichloroimidazoles and their antimicrobial,protistocidal, and fungistatic properties

Previously unknown 1-alkyl-, 1-benzyl-, and 1-aryloxyethylderivatives of dichloroimidazoles and products of their structural transformation were synthesized from 4,5-dichloroimidazole or 2-methyl-4,5- dichloroimidazole using alkyl, benzyl or aryloxyethyl halides. These N-substituted compounds were shown to have a weak antibacterial activity against some pathogenic gram-positive and gram-negative bacteria (Staphylococcus aureus and Escherichia coli). At the same time, some of the obtained compounds demonstrated a significant protistocidal activity against Colpoda steinii, which can exceed in strength the activity of clinically used veterinary drug Baycox. Moreover, these compounds showed a pronounced fungistatic effect.     

Toxicity of N-substituted aromatics to acetoclastic methanogenic activity in granular sludge.

N-substituted aromatics are important priority pollutants entering the environment primarily through anthropogenic activities associated with the industrial production of dyes, explosives, pesticides, and pharmaceuticals. Anaerobic treatment of wastewaters discharged by these industries could potentially be problematical as a result of the high toxicity of N-substituted aromatics. The objective of this study was to examine the structure-toxicity relationships of N-substituted aromatic compounds to acetoclastic methanogenic bacteria. The toxicity was assayed in serum flasks by measuring methane production in granular sludge. Unacclimated cultures were used to minimize the biotransformation of the toxic organic chemicals during the test. The nature and the degree of the aromatic substitution were observed to have a profound effect on the toxicity of the test compound. Nitroaromatic compounds were, on the average, over 500-fold more toxic than their corresponding aromatic amines. Considering the facile reduction of nitro groups by anaerobic microorganisms, a dramatic detoxification of nitroaromatics towards methanogens can be expected to occur during anaerobic wastewater treatment. While the toxicity exerted by the N-substituted aromatic compounds was closely correlated with compound apolarity (log P), it was observed that at any given log P, N-substituted phenols had a toxicity that was 2 orders of magnitude higher than that of chlorophenols and alkylphenols. This indicates that toxicity due to the chemical reactivity of nitroaromatics is much more important than partitioning effects in bacterial membranes.     

An investigation of the N-demethylation of 3-deoxymorphine and the affinity of the alkylation products to mu, delta, and kappa receptors

The N-demethylation of 3-deoxymorphine (1) was investigated using methyl chloroformate and hydrazine. 3-Deoxynormorphine (2) was obtained in 70% yield, and 3-deoxydihydronormorphine (3) was also obtained as a side product. The mu, delta, and kappa receptor binding affinity of a series of N-substituted 3-deoxynormorphines 6 and 7 and N-substituted 3-deoxydihydronormorphines 8-11 was also determined.     

Synthesis and spectroelectrochemistry of N-cobaltacarborane porphyrin conjugates

N-Substituted porphyrins are well-known for the distortion they exhibit of the porphyrin plane through the sp(3) hybridization of one of the pyrrolenic units. They have served as model compounds in investigations of many biochemical processes. In this paper, we developed an efficient route to N-substituted porphyrins, and report the synthesis of a series of new N-substituted cobaltacarborane-porphyrins containing one or two cobaltabisdicarbollide anions linked by (CH(2)CH(2)O)(2) chains to either the core porphyrin nitrogens or to a meso-aminophenyl group. These conjugates show different degrees of distortion of the porphyrin macrocycle, which affect their spectroscopic and electrochemical properties. In particular, the core N-substituted conjugates show significant fluorescence quenching in comparison with the noncore substituted macrocycles. The X-ray structures of two targeted core N-cobaltacarborane porphyrin conjugates are presented. The electrochemical and spectroelectrochemical properties of these porphyrin conjugates were investigated; while the peripheral N-substituted cobaltacarboranylporphyrins undergo three reversible reductions and three reversible oxidations (two attributed to the porphyrin and one to the Co(III) cluster), the core N-substituted porphyrins exhibit complicated electrochemical behavior with coupled chemical reactions.     

Studies on Nicotinoids as an Insecticide

The structure-toxicity relationship of pyridylalkylamine: N-substituted and unsubstituted 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, 3-pyridylethyl- and 3-pyridyl-butyl-amines, was reinvestigated based on the insecticidal activities against house fly, Musca domestica L., obtained by the topical application method. The highest toxicities were seen in the N-substituted 3-pyridylmethylamine series which were provided with the highly basic nitrogen.     

Exploration of a new series of CCR5 antagonists: Multi-dimensional optimization of a sub-series containing N-substituted pyrazoles

The introduction of N-substituted pyrazoles in a new series of CCR5 antagonists was shown to substantially increase antiviral activity.