First synthesis of racemic saphenamycin and its enantiomers. investigation of biological activity

The natural antibiotic saphenamycin, 6-[1-(2-hydroxy-6-methyl-benzoyloxy)-ethyl]-phenazine-1-carboxylic acid, was synthesized from saphenic acid using temporary allyl protection of carboxy and phenoxy functionalities. Resolution of racemic saphenic acid was performed by crystallization of the corresponding (-)-brucine diastereomeric salts and the absolute configuration of (-)-brucinium (-)-saphenate was determined by X-ray crystallography to have R-configuration. This also proved to be the configuration of natural saphenic acid. Enantiomers of saphenamycin were obtained from resolved saphenic acid and screened against a range of skin flora and resistant Staphylococcus aureus strains. Biological activities of saphenamycin enantiomers were compared with that of the synthetic racemate as well as earlier reported activities of saphenamycin isolated from natural sources. No significant difference was observed in activity of the enantiomers of saphenamycin, which revealed that the chirality of saphenamycin has no consequences for the antibiotic activity. Saphenamycin proved to be a potent antibiotic against fusidic acid and rifampicin resistant S. aureus strains showing MIC of 0.1-0.2 microg/mL.     

Green synthesis of tetrahydropyrimidine analogues and evaluation of their antimicrobial activity

It is the first report of 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines derivatives, catalyzed by ZrOCl₂. The mild reaction conditions, excellent yields in shorter reaction time and evasion of cumbersome workup procedures make this process economically lucrative for industrial application. The novelty and highlight of the present method is the promising antibacterial and antifungal activity shown by compounds (4a, 4b, 4e, 4f, 4h and 4l) compared to standard.     

A new synthesis of the tripeptide Gly-His-Lys with antimicrobial activity

Summary A new solid phase synthesis of the growth-modulating tripeptide Gly-His-Lys is described. 2-Chlorotrityl chloride resin and 9-fluorenylmethoxycarbonyl-(Fmoc), 4-methyltrityl-(Mtt) protecting groups were used. The synthetic tripeptide was tested for its activity against bacteria, yeast and fungi. The in vitro effect of the tripeptide on DNA, RNA and protein synthesis was studied as well.     

Solid-phase synthesis of 5'-deoxy-5'-amino-clitocine analogues

Several 6-substituted-amino-5'-deoxy-5'-amino-clitocine analogues were synthesized in a parallel fashion in solid phase. The desired scaffold was generated by coupling 2,3-O-bis-(t-butyldimethylsilyl)-5-N-(monomethoxytrityl-polystyrene-resin)-1,5-diamino-5-deoxy-beta-D-ribofuranose and 4, 6-dichloro-5-nitropyrimidine. The scaffold was then reacted with a variety of amines to generate a small library of 14 analogues of 5'-deoxy-5'-amino-clitocine following a protocol developed earlier.     

A new class of nifuroxazide analogues: synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus

Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been an increasing problem worldwide since the initial reports over 40 years ago. To examine new drug leads with potential antibacterial activities, 14 p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides were designed, synthesized, and tested against standard and multidrug-resistant S. aureus strains by serial dilution tests. All compounds exhibited significant bacteriostatic activity and some of them also showed bactericidal activity. The results confirmed the potential of this class of compounds as an alternative for the development of selective antimicrobial agents.     

Synthetic magainin analogues with improved antimicrobial activity

Based on modifications to enhance the alpha-helical structure of the broad spectrum antibiotic magainin 2, a series of analogues have been synthesized which display an increase up to two orders of magnitude in antimicrobial activity and, in the most favorable case, no appreciable increase in hemolytic activity over magainin 1 at the concentrations tested.     

Solid-phase total synthesis and antimicrobial activities of loloatins A-D

The first total synthesis of the decapeptide antibiotics loloatins A-D (1-4), originally isolated from the marine bacterial isolate MK-PNG-276A, possibly in the genus Bacillus, was accomplished by solid-phase peptide synthesis (SPPS), followed by 'head-to-tail' cyclization of the activated linear precursors, without protection of nucleophilic side-chain functions, on a safety-catch resin. The synthetic peptides were equally active as the natural products isolated from the bacterial source and found to possess similar bacterial selectivity as other members in the family of amphipathic antimicrobial cyclic decapeptides.     

Solid-phase synthesis of polymyxin B1 and analogues via a safety-catch approach.

As part of a program towards the development of novel antibiotics, a convenient method for solid-phase synthesis of the cyclic cationic peptide polymyxin B1 and analogues thereof is described. The methodology, based on cleavage-by-cyclization using Kenner's safety-catch linker, yields crude products with purities ranging from 37-67%. Antibacterial assays revealed that analogues 23-26, in which the (S)-6-methyloctanoic acid moiety is replaced with shorter acyl chains, exhibit distinct antimicrobial activity. The results suggest that the length of the acyl chain is rather critical for antimicrobial activity. On the other hand, substitution of the hydrophobic ring-segment D-Phe-6/Leu-7 in polymyxin B1 with dipeptide mimics (i.e. analogues 27-33) resulted in almost complete loss of antimicrobial activity.     

Design of novel analogues of short antimicrobial peptide anoplin with improved antimicrobial activity

Currently, novel antibiotics are urgently required to combat the emergence of drug‐resistant bacteria. Antimicrobial peptides with membrane‐lytic mechanism of action have attracted considerable interest. Anoplin, a natural α‐helical amphiphilic antimicrobial peptide, is an ideal research template because of its short sequence. In this study, we designed and synthesized a group of analogues of anoplin. Among these analogues, anoplin‐4 composed of d ‐amino acids displayed the highest antimicrobial activity due to increased charge, hydrophobicity and amphiphilicity. Gratifyingly, anoplin‐4 showed low toxicity to host cells, indicating high bacterial selectivity. Furthermore, the mortality rate of mice infected with Escherichia coli was significantly reduced by anoplin‐4 treatment relative to anoplin. In conclusion, anoplin‐4 is a novel anoplin analogue with high antimicrobial activity and enzymatic stability, which may represent a potent agent for the treatment of infection. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

Solid-phase synthesis of new pyrrolobenzodiazepine-chalcone conjugates: DNA-binding affinity and anticancer activity

A new class of C8-linked pyrrolo[2,1-c][1,4]benzodiazepine-chalcone conjugates have been prepared by employing a solid-phase synthetic protocol. In this strategy an intramolecular aza-Wittig reductive cyclization approach has been utilized. Interestingly, some of these molecules have shown enhanced DNA-binding affinity and promising anticancer activity on a large number of human cancer cell lines.     

Design,synthesis and evaluation of antimicrobial activity of N-terminal modified Leucocin A analogues

Class IIa bacteriocins are potent antimicrobial peptides produced by lactic acid bacteria to destroy competing microorganisms. The N-terminal domain of these peptides consists of a conserved YGNGV sequence and a disulphide bond. The YGNGV motif is essential for activity, whereas, the two cysteines involved in the disulphide bond can be replaced with hydrophobic residues. The C-terminal region has variable sequences, and folds into a conserved amphipathic α-helical structure. To elucidate the structure–activity relationship in the N-terminal domain of these peptides, three analogues (1–3) of a class IIa bacteriocin, Leucocin A (LeuA), were designed and synthesized by replacing the N-terminal β-sheet residues of the native peptide with shorter β-turn motifs. Such replacement abolished the antibacterial activity in the analogues, however, analogue 1 was able to competitively inhibit the activity of native LeuA. Native LeuA (37-mer) was synthesized using native chemical ligation method in high yield. Solution conformation study using circular dichroism spectroscopy and molecular dynamics simulations suggested that the C-terminal region of analogue 1 adopts helical folding as found in LeuA, while the N-terminal region did not fold into β-sheet conformation. These structure–activity studies highlight the role of proper folding and complete sequence in the activity of class IIa bacteriocins.     

Solid-phase synthesis and antibacterial activity of hydroxycinnamic acid amides and analogues against methicillin-resistant Staphylococcus aureus and vancomycin-resistant S. aureus

A library of hydroxycinnamic acid amides (HCAAs) and analogues were synthesized using solid-phase synthesis technique. These compounds were screened for antibacterial against methicillin-resistant Staphylococcus aureus (MRSA) (11 strains) and vancomycin-resistant S. aureus (VRSA) (4 strains). Dihydrocaffeoyl analogues showed activity against VRSA which were better than the reference drugs, vancomycin and oxacillin. These compounds also exhibited antibacterial activity against MRSA, which were more potent than oxacillin.     

Solid-phase synthesis of a combinatorial library of dihydroceramide analogues and its activity in human alveolar epithelial cells

Solid-phase synthesis of a small combinatorial library of dihydroceramide analogues as mixtures of erythro and threo diastereomers is described. Some dihydroceramide analogues cause growth arrest and apoptosis in a dose-dependent manner in human alveolar epithelial cells. This activity is likely due to the threo isomers, as evidenced by cellular studies with a pair of diastereomerically pure N-acyldihydrosphingosines. The apoptotic activity reported in this work provides information for the design of new compounds that may provide the basis for the generation of biochemical tools for the study of different pathologies where ceramide and/or dihydroceramide are involved.     

Synthesis and antimicrobial activity of novel globomycin analogues

Globomycin, a signal peptidase II inhibitor, and its derivatives show potent antibacterial activity against Gram-negative bacteria. The synthesis and antimicrobial activity of novel globomycin analogues are reported. One of the analogues showed a more potent activity against Gram-negative bacteria than globomycin and also exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).     

Synthesis,biological activity and solution structure of new analogues of the antimicrobial Gramicidin S

Gramicidin S (GS) is a cyclo‐decapeptide antibiotic isolated from Bacillus brevis. The structural studies have shown that GS forms a two‐stranded antiparallel β‐sheet imposed by two II′ β‐turns. Despite its wide Gram+ and Gram? antimicrobial spectrum, GS is useless in therapy because of its high hemotoxicity in humans. It was found, however, that the analogues of GS‐14 (GS with 14 amino acid residues) attained a better antimicrobial selectivity when their amphipatic moments were perturbed. In this study, we report effects of similar perturbations imposed on GS cyclo‐decapeptide analogues. Having solved their structures by NMR/molecular dynamics and having tested their activities/selectivities, we have concluded that the idea of perturbation of the amphipatic moment does not work for GS‐10_0 analogues. An innovative approach to the synthesis of head‐to‐tail cyclopeptides was used. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis and antimicrobial activity of dermaseptin S1 analogues

Dermaseptins are peptides found in the skin secretions of Phyllomedusinae frogs. These peptides exert lytic action on some microorganisms without substantial haemolysis. In an attempt to understand the antimicrobial activity of these peptides we designed several dermaseptin S1 (ALWKTMLKKLGTMALHAGKAALGAAADTISQGTQ) (DS1) analogues. All peptides were tested on the growth of prokaryotic (Gram-positive and Gram-negative bacteria) and eukaryotic (the yeast Candida albicans and the protozoon Leishmania major) organisms. Our data showed a dose-dependent killing effect by most DS1 derivatives. Maximal antibacterial activity was displayed by a 16-mer peptide that was more active than native DS1.     

The synthesis and biological activity of alkyloxy prostaglandin analogues.

Prostaglandin analogues in which the alkyl chain attached to C-15 in the natural compounds is replaced by an alkyoxyalkyl group have been synthesised. Compounds of the 17-oxa series are particularly potent luteolytic agents and are selective in the sense that they are less effective than PGE-2alpha in causing isotonic contractions of isolated uterus muscle.     

Solid-phase synthesis and biochemical evaluation of conformationally constrained analogues of deglycobleomycin A5

Deglycobleomycin binds to and degrades the self-complementary oligonucleotide d(CGCTAGCG)(2) in a sequence selective fashion. A previous modeling study [J. Am. Chem. Soc. 120, (1998), 7450] had shown that, during binding to double stranded DNA, the conformation of the methylvalerate domain of deglycoBLM approximated that of S-proline. In the belief that an analogue of deglycoBLM structurally constrained to mimic the DNA-bound conformation might exhibit facilitated DNA binding and cleavage, an analogue of deglycoBLM was prepared in which the methylvalerate moiety was replaced by S-proline. This deglycoBLM analogue, as well as the related analogue containing R-proline, was synthesized on a TentaGel resin. Both of the analogues were found to be capable of binding Fe(2+) and activating O(2) for transfer to styrene. However, both deglycoBLM analogues exhibited diminished abilities to effect the relaxation of supercoiled plasmid DNA, and neither mediated sequence selective DNA cleavage.     

Solid-phase synthesis of methyl carboxymycobactin T 7 and analogues as potential antimycobacterial agents

A solid-phase approach for the total synthesis of methyl carboxymycobactins 1a-d, with an on-resin cyclization leading to azopine 5 as the key step, was developed. The iron-affinity of these compounds was assessed by a competitive sulfoxine-binding assay, and antimycobacterial activity was tested against the growth of Mycobacterium avium.     

Efficient synthesis of fluorothiosparfosic acid analogues with potential antitumoral activity

In this paper, we describe a short synthesis of N-(phosphonoacetyl)-L-aspartate (PALA) analogues. The mono- and difluorinated thioacetamide precursors were prepared in one step from methyl (diethoxyphosphono)di- and monofluoromethyldithioacetates 8 and 11 as starting materials. Antiproliferating properties on a L1210 strain and ATCase inhibition of these new compounds are disclosed. ThioPALA(FF) 5c showed a remarkable cytotoxic activity towards murine leukemia L1210, when used as tetraester.