Untying the anchor for the lipopolysaccharide: lipid A structural modification systems offer diagnostic and therapeutic options to tackle polymyxin resistance.

Polymyxin antibiotics are the last resort for treating patients in intensive care units infected with multiple-resistant Gram-negative bacteria. Due to their polycationic structure, their mode of action is based on an ionic interaction with the negatively charged lipid A portion of the lipopolysaccharide (LPS). The most prevalent polymyxin resistance mechanisms involve covalent modifications of lipid A: addition of the cationic sugar 4-amino-L-arabinose (L-Ara4N) and/or phosphoethanolamine (pEtN). The modified structure of lipid A has a lower net negative charge, leading to the repulsion of polymyxins and bacterial resistance to membrane disruption. Genes encoding the enzymatic systems involved in these modifications can be transferred either through chromosomes or mobile genetic elements. Therefore, new approaches to resistance diagnostics have been developed. On another note, interfering with these enzymatic systems might offer new therapeutic targets for drug discovery. This literature review focuses on diagnostic approaches based on structural changes in lipid A and on the therapeutic potential of molecules interfering with these changes.

Search for new antimicrobials: spectroscopic, spectrometric, and in vitro antimicrobial activity investigation of Ga(III) and Fe(III) complexes with aroylhydrazones.

The in vitro antimicrobial activity of Fe(III) and Ga(III) complexes with N'-(2,3-dihydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (H2L1), N'-(2,4-dihydroxy-phenyl-methylidene)-3-pyridinecarbohydrazide (H2L2), N'-(2,5-dihydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (H2L3), N'-(2-hydroxy-3-methoxyphenyl-methylidene)-3-pyridine-carbohydrazide (H2L4), N'-(2-hydroxy-4-methoxyphenylmethyl-idene)-3-pyridine-carbohydrazide (H2L5), and N'-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbo-hydrazide (H2L6) toward several Gram-positive strains of Staphylococcus aureus, a Gram-negative strain of Escherichia coli, and a yeast Candida albicans were investigated. Fe(III)-complexes do not possess antimicrobial activity against all tested strains at concentrations up to 10 mg mL-1. Ga(III) complexes with dihydroxy derivatives showed selective activity, while the broadest range of antibacterial and antifungal activities was observed for complex with 2-hydroxy-3-methoxy-derivative, ligand H2L5. In addition, the coordination properties of ligands H2L1-H2L3 in solution were investigated by UV-Vis spectroscopy. The stability constants (logK) for Ga(III)-H2L 1:1 complexes in MeOH/H2O 1/1 at pH 2.52 were determined, and amounted to 5.8, 5.68, and 4.7, respectively. Detailed characterization of complexes was performed by high-resolution mass spectrometry. The fragmentation pathways for dimer [Fe2(L1)2]2+, [Fe(HL)2]+, [Ga(HL2)2]+ and adduct ions are given. The comparison with analogue Ga(III) and Fe(III) complexes with compounds H2L4-H2L6 was made as well.

Innovative Insights into In Vitro Activity of Colloidal Platinum Nanoparticles against ESBL-Producing Strains of Escherichia coli and Klebsiella pneumoniae.

Growing morbidity and mortality rates due to increase in the number of infections caused by MDR (multi-drug resistant) microorganisms are becoming some of the foremost global health issues. Thus, the need to search for and find novel approaches to fight AMR (antimicrobial resistance) has become obligatory. This study aimed to determine the antimicrobial properties of commercially purchased colloidal platinum nanoparticles by examining the existence and potency of their antibacterial effects and investigating the mechanisms by means of which they express these activities. Antimicrobial properties were investigated with respect to standard laboratory ATCC (American Type Cell Culture) and clinical extended-spectrum beta-lactamase (ESBL)-producing strains of Escherichia (E.) coli and Klebsiella (K.) pneumoniae. Standard microbiological methods of serial microdilution, modulation of microbial cell death kinetics ("time-kill" assays), and biofilm inhibition were used. Bacterial cell wall damage and ROS (reactive oxygen species) levels were assessed in order to explore the mechanisms of platinum nanoparticles' antibacterial activities. Platinum nanoparticles showed strong antibacterial effects against all tested bacterial strains, though their antibacterial effects were found to succumb to time kinetics. Antibiofilm activity was modest overall and significantly effective only against E. coli strains. By measuring extracellular DNA/RNA and protein concentrations, induced bacterial cell wall damage could be assumed. The determination of ROS levels induced by platinum nanoparticles revealed their possible implication in antibacterial activity. We conclude that platinum nanoparticles exhibit potent antibacterial effects against standard laboratory and resistant strains of E. coli and K. pneumoniae. Both, cell wall damage and ROS induction could have important role as mechanisms of antibacterial activity, and, require further investigation.

Globularia alypum L. and Related Species: LC-MS Profiles and Antidiabetic, Antioxidant, Anti-Inflammatory, Antibacterial and Anticancer Potential.

Species from the genus Globularia L. have been used as healing agents for various ailments, with utilization of Globularia alypum L. being most frequently reported. The aim of this study was to evaluate the antidiabetic, antioxidant, anti-inflammatory, antibacterial and anticancer potential of G. alypum and three related species, G. punctata Lapeyr., G. cordifolia L. and G. meridionalis (Podp.) O.Schwarz, in relation to their phytochemical compositions. Globularin and verbascoside were identified using LC-PDA-ESI-MSn as the major metabolites of G. alypum with known biological activities. G. alypum demonstrated the greatest α-glucosidase inhibitory activity and DPPH radical scavenging activity (IC50 = 17.25 µg/mL), while its anti-inflammatory activity was not significantly different from those of related species. All investigated species showed considerable antibacterial activity against methicillin-resistant Staphylococcus aureus in the broth microdilution method (MIC = 1.42-3.79 mg/mL). G. punctata also showed antibacterial activities against Escherichia coli (MIC = 1.42 mg/mL), Bacillus subtilis (MIC = 1.89 mg/mL), B. cereus (MIC = 2.84 mg/mL) and Enterococcus faecalis (MBC = 5.68 mg/mL). G. punctata, G. cordifolia and G. meridionalis showed greater anticancer potential than G. alypum. Obtained results indicate investigated Globularia species could serve as sources of diverse bioactive molecules, with G. punctata having the greatest antibacterial potential.

Antibacterial Fractions from Erodium cicutarium Exposed-Clinical Strains of Staphylococcus aureus in Focus.

Followed by a buildup of its phytochemical profile, Erodium cicutarium is being subjected to antimicrobial investigation guided with its ethnobotanical use. The results of performed in vitro screening on Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans strains, show that E. cicutarium has antimicrobial activity, with a particular emphasis on clinical S. aureus strains-both the methicillin sensitive (MSSA) and the methicillin resistant (MRSA) S. aureus. Experimental design consisted of general methods (the serial microdilution broth assay and the agar well diffusion assay), as well as observing bactericidal/bacteriostatic activity through time (the "time-kill" assay), investigating the effect on cell wall integrity and biofilm formation, and modulation of bacterial hemolysis. Observed antibacterial activity from above-described methods led to further activity-guided fractionation of water and methanol extracts using bioautography coupled with UHPLC-LTQ OrbiTrap MS4. It was determined that active fractions are predominantly formed by gallic acid derivatives and flavonol glycosides. Among the most active phytochemicals, galloyl-shikimic acid was identified as the most abundant compound. These results point to a direct connection between galloyl-shikimic acid and the observed E. cicutarium antibacterial activity, and open several new research approaches for future investigation.

Antifungal and Anti-Virulent Activity of Origanum majorana L. Essential Oil on Candida albicans and In Vivo Toxicity in the Galleria mellonella Larval Model.

The aim of this study was to investigate and compare in detail both the antifungal activity in vitro (with planktonic and biofilm-forming cells) and the essential oil composition (EOs) of naturally growing (OMN) and cultivated (OMC) samples of Origanum majorana L. (marjoram). The essential oil composition was analyzed using GC-MS. The major constituent of both EOs was carvacrol: 75.3% and 84%, respectively. Both essential oils showed high antifungal activity against clinically relevant Candida spp. with IC50 and IC90 less than or equal to 0.5 µg mL-1 and inhibition of biofilm with a concentration of 3.5 µg mL-1 or less. Cultivated marjoram oil showed higher anti-biofilm activity against C. albicans. In addition, OMC showed greater inhibition of germ-tube formation (inhibition by 83% in Spider media), the major virulence factor of C. albicans at a concentration of 0.125 µg mL-1. Both EOs modulated cell surface hydrophobicity (CSH), but OMN proved to be more active with a CSH% up to 58.41%. The efficacy of O. majorana EOs was also investigated using Galleria mellonella larvae as a model. It was observed that while the larvae of the control group infected with C. albicans (6.0 × 108 cells) and not receiving treatment died in the controls carried out after 24 h, all larvae in the infected treatment group survived at the end of the 96th hour. When the treatment group and the infected group were evaluated in terms of vital activities, it was found that the difference was statistically significant (p < 0.001). The infection of larvae with C. albicans and the effects of O. majorana EOs on the hemocytes of the model organism and the blastospores of C. albicans were evaluated by light microscopy on slides stained with Giemsa. Cytological examination in the treatment group revealed that C. albicans blastospores were phagocytosed and morphological changes occurred in hemocytes. Our results indicated that the essential oil of both samples showed strong antifungal activities against planktonic and biofilm-forming C. albicans cells and also had an influence on putative virulence factors (germ-tube formation and its length and on CSH).

Nonaqueous Polyethylene Glycol as a Safer Alternative to Ethanolic Propolis Extracts with Comparable Antioxidant and Antimicrobial Activity.

We compared the chemical composition, antioxidant and antimicrobial activity of two propolis extracts: one obtained with nonaqueous polyethylene glycol, PEG 400 (PgEP), and the other obtained with ethanol (EEP). We analyzed the total phenolic content (TPC) and the concentrations of ten markers of propolis antioxidant activity with HPLC-UV: caffeic acid, p-coumaric acid, trans-ferulic acid, trans-cinnamic acid, kaempferol, apigenin, pinocembrin, chrysin, CAPE, and galangin. Antioxidant activity was tested using DPPH and FRAP assay, and antimicrobial activity was assessed through minimum inhibitory concentrations (MICs) and minimum biofilm eradication concentration (MBEC) determination. Maceration gave the yield of propolis of 25.2 ± 0.08% in EEP, and 21.5 ± 0.24% in PgEP. All ten markers of antioxidant activity were found in both extracts, with all marker concentrations, except kaempferol, higher in EEP. There was no significant difference between the TPC and antioxidant activity of the PgEP and the EEP extract; TPC of PgEP was 16.78 ± 0.23 mg/mL, while EEP had TPC of 15.92 ± 0.78 mg/mL. Both extracts had antimicrobial activity against most investigated pathogens and Staphylococcus aureus, Acinetobacter baumannii, and Escherichia coli biofilms. EEP was more effective against all tested susceptible pathogens, except E. coli, possibly due to higher content of kaempferol in PgEP relative to other polyphenols. Nonaqueous PEG 400 could be used for propolis extraction. It gives extracts with comparable concentrations of antioxidants and has a good antioxidant and antimicrobial activity. It is a safe excipient, convenient for pediatric and veterinary formulations.

In Vitro Confirmation of Siramesine as a Novel Antifungal Agent with In Silico Lead Proposals of Structurally Related Antifungals.

The limited number of medicinal products available to treat of fungal infections makes control of fungal pathogens problematic, especially since the number of fungal resistance incidents increases. Given the high costs and slow development of new antifungal treatment options, repurposing of already known compounds is one of the proposed strategies. The objective of this study was to perform in vitro experimental tests of already identified lead compounds in our previous in silico drug repurposing study, which had been conducted on the known Drugbank database using a seven-step procedure which includes machine learning and molecular docking. This study identifies siramesine as a novel antifungal agent. This novel indication was confirmed through in vitro testing using several yeast species and one mold. The results showed susceptibility of Candida species to siramesine with MIC at concentration 12.5 µg/mL, whereas other candidates had no antifungal activity. Siramesine was also effective against in vitro biofilm formation and already formed biofilm was reduced following 24 h treatment with a MBEC range of 50-62.5 µg/mL. Siramesine is involved in modulation of ergosterol biosynthesis in vitro, which indicates it is a potential target for its antifungal activity. This implicates the possibility of siramesine repurposing, especially since there are already published data about nontoxicity. Following our in vitro results, we provide additional in depth in silico analysis of siramesine and compounds structurally similar to siramesine, providing an extended lead set for further preclinical and clinical investigation, which is needed to clearly define molecular targets and to elucidate its in vivo effectiveness as well.

Development of Antibacterial Protective Coatings Active against MSSA and MRSA on Biodegradable Polymers.

In this work the in vitro antimicrobial activity of colloidal solutions of nine different commercially available nanoparticles were investigated against Staphylococcus aureus strains, both methicillin-sensitive (MSSA) and methicillin-resistant (MRSA). Research covered antimicrobial investigation of different metal and metal-oxide nanoparticles, including Ag 10 nm, Ag 40 nm, Al2O3 100 nm, Au 20 nm, Pt 4 nm, TiO2 100 nm, Y2O3 100 nm, ZnO 100 nm and ZrO2 100 nm nanoparticles. Such materials were foreseen to be applied as coatings on 3D-printed biodegradable polymers: i.e., catheters, disposable materials, hospital bedding items, disposable antimicrobial linings and bandages for chronic wounds. Therefore, the antimicrobial activity of the nanoparticles was determined by agar well diffusion assays and serial microdilution broth assays. In addition, the chromatographic characterization of elements present in trace amounts was performed as a method for tracing the nanoparticles. Moreover, the potential of preparing the rough surface of biodegradable polymers for coating with antimicrobial nanoparticles was tested by 3D-printing fused deposition methodology. The in vitro results have shown that particular nanoparticles provided powerful antimicrobial effects against MSSA and MRSA strains, and can be easily applied on different biopolymers.

Protective effects of olive oil phenolics oleuropein and hydroxytyrosol against hydrogen peroxide-induced DNA damage in human peripheral lymphocytes.

This study investigates antioxidant capacity and protective effects of phenolic compounds oleuropein (OLP) and hydroxytyrosol (HT), present in olive oil and olive leaves, against H2O2-induced DNA damage in human peripheral lymphocytes. Antioxidant potency was determined using the measurement of radical-scavenging activity (ABTS∙+ assay), ferric reducing power (FRAP assay) and cupric reducing antioxidant capacity (CUPRAC assay). Both substances were found to be potent antioxidant agents due to their free radical-scavenging activities. Antigenotoxic effects of oleuropein and hydroxytyrosol against H2O2-induced damage in human lymphocytes were evaluated in vitro by alkaline comet assay. At tested concentrations (1, 5, 10 µmol L-1), oleuropein and hydroxytyrosol did not induce a significant increase of primary DNA damage in comparison with the negative control. Pretreatment of human lymphocytes with each of the substances for 120 min produced a dose-dependent reduction of primary DNA damage in the tested cell type. Hydroxytyrosol showed a better protective effect against H2O2-induced DNA breaks than oleuropein which could be associated with their free radical-scavenging efficacy.

Design and synthesis of novel antimicrobial peptide scaffolds.

Muramic acid (Mur), a sugar amino acid (SAA), is present in the cell walls of bacteria asN-acetyl muramic acid (MurNAc) where together with ofN-acetylglucosamine (GlcNAc) and peptide makes main building block of peptidoglycan (PGN). It was challenging to incorporate muramic acid as SAA characteristic for bacteria into the peptides and investigate the antimicrobial activity of these scaffolds. Four building units were used in designing the desired peptide: muramic acid, tetrapeptide Leu-Ser-Lys-Leu, Nε-Lys, and Asn. Positions of three components were changeable while the position of Asn was always C-terminal (in linear peptides). The glycopeptide libraries of linear and cyclic peptides were synthesized using solid-phase peptide synthesis (SPPS). The antimicrobial effect of linear and cyclic glycopeptides, as well as the LSKL sequence used as a control, was investigated on several standard laboratory microbial strains. Liner glycopeptide with sequences Leu-Ser-Lys-Leu-Nε-Lys-Mur-Asn was active onStaphylococcus aureus(Gram-positive bacteria). Prepared compounds did not show activity towards applied tumor and normal human cell lines.

First Extensive Polyphenolic Profile of Erodium cicutarium with Novel Insights to Elemental Composition and Antioxidant Activity.

Erodium cicutarium is known for its total polyphenolic content, but this work reveals the first highly detailed profile of E. cicutarium, obtained with UHPLC-LTQ OrbiTrap MS4 and UHPLC-QqQ-MS/MS techniques. A total of 85 phenolic compounds were identified and 17 constituents were quantified. Overall, 25 new compounds were found, which have not yet been reported for the Erodium genera, or the family Geraniaceae. Along with methanolic extracts, the so far poorly investigated water extracts exhibited in vitro antioxidant activity according to all performed assays, including the ferric reducing/antioxidant power assay (FRAP), 2,2-diphenyl-1-picrylhydrazyl assay (DPPH), 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) assay (ABTS) and cupric ion reducing antioxidant capacity assay (CUPRAC). Elemental composition analysis performed with inductively coupled plasma atomic emission spectrometry (ICP-AES) and, additionally, hydride generation atomic absorption spectrometry (HydrEA-ETAAS) showed six most abundant elements to be decreasing as follows: Mg>Ca>K>S>P>Na, and gave first data regarding inorganic arsenic content (109.3-248.4 ng g-1 ). These results suggest E. cicutarium to be a valuable source of various phenolic compounds with substantial potential for further bioactivity testing.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-7.

Breakthroughs in Medicinal Chemistry [...].

Antimicrobial assesment of aroylhydrazone derivatives in vitro.

Aroylhydrazones 1-13 were screened for antimicrobial and antibiofilm activities in vitro. N'-(2-hydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (2), N'-(5-chloro-2-hydroxyphenyl-methylidene)-3-pyridinecarbohydrazide (10), N'-(3,5-chloro-2-hydroxyphenylmethylidene)-3-pyridinecarbohydrazide (11), and N'-(2-hydroxy-5-nitrophenylmethylidene)-3-pyridinecarbohydrazide (12) showed antibacterial activity against Escherichia coli, with MIC values (in µmol mL-1) of 0.18-0.23, 0.11-0.20, 0.16-0.17 and 0.35-0.37, resp. Compounds 11 and 12, as well as N'-(2-hydroxy-3-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (6) and N'-(2-hydroxy-5- methoxyphenylmethylidene)-3-pyridinecarbohydrazide (8) showed antibacterial activity against Staphylococcus aureus, with the lowest MIC values of 0.005-0.2, 0.05-0.12, 0.06-0.48 and 0.17-0.99 µmol mL-1. N'-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (7) showed antifungal activity against both fluconazole resistant and susceptible C. albicans strains with IC90 range of 0.18-0.1 µmol mL-1. Only compound 11 showed activity against C. albicans ATCC 10231 comparable to the activity of nystatin (the lowest MIC 4.0 ×10-2 vs. 1.7 × 10-2 µmol mL-1). Good activity regarding multi-resistant clinical strains was observed for compound 12 against MRSA strain (MIC 0.02 µmol mL-1) and compounds 2, 6 and 12 against ESBL+ E. coli MFBF 12794, with the lowest MIC for compound 12 (IC50 0.16 µmol mL-1). Anti-biofilm activity was found for compounds 2 (MBFIC 0.015-0.02 µmol mL-1 against MRSA) and 12 (MBFIC 0.013 µmol mL-1 against EBSL+ E. coli). In the case of compound 2 against MRSA biofilm formation, MBFIC values were comparable to those of gentamicin sulphate, whereas in the case of compound 12 and EBSL+ E. coli even more favourable activity compared to gentamicin was observed.

Inhibition of Satellite RNA Associated Cucumber Mosaic Virus Infection by Essential Oil of Micromeria croatica (Pers.) Schott.

The present results dealing with the antiphytoviral activity of essential oil indicate that these plant metabolites can trigger a response to viral infection. The essential oil from Micromeria croatica and the main oil components ß-caryophyllene and caryophyllene oxide were tested for antiphytoviral activity on plants infected with satellite RNA associated cucumber mosaic virus. Simultaneous inoculation of virus with essential oil or with the dominant components of oil, and the treatment of plants prior to virus inoculation, resulted in a reduction of virus infection in the local and systemic host plants. Treatment with essential oil changed the level of alternative oxidase gene expression in infected Arabidopsis plants indicating a connection between the essential oil treatment, aox gene expression and the development of viral infection.

Multicomponent Approach to a Library of N-Substituted γ-Lactams.

The γ-lactam motif is often found in naturally occurring compounds with diverse biological activities. We prepared a 28-member library of N-substituted γ-lactams following a single-pot, three-component Ugi reaction comprising bifunctional building block, l-glutamic acid methyl ester. The reaction tolerates structurally diverse carbonyl and isocyanide components providing a robust access to functionalized γ-lactams. Antimicrobial susceptibility testing, including agar well diffusion assay, serial microdilution broth assay, and antibiofilm activity testing, identified a potent compound with antibiofilm activity against Staphylococcus aureus ATCC 6538.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].

Antifungal activity of some Sternbergia taxa: effects on germ tube and biofilm formation

Natural products are rapidly becoming the primary sources of novel antimicrobial agents, as resistance to existing antimicrobial agents is increasing. Apart from determining the antimicrobial activity of natural products, it is also important to understand their effects on the virulence factors of microorganisms. This study aimed to determine the antimicrobial activity of Sternbergia species prevalent in Turkey and investigate their role in the inhibition of germination tube and biofilm formation, both of which are known to be important virulence factors of Candida albicans. The antimicrobial activities of the plant extracts were evaluated using bore-plate and broth microdilution method. The extracts' capacity to inhibit the formation of the germ-tube was also evaluated. The findings of our study revealed that Sternbergia lutea, Sternbergia vernalis possessed antimicrobial activities, with MIC values ranging between 0.048 mg/mL and 0.39 mg/mL. The highest antimicrobial activity was observed against Candida dubliniensis (0.048 mg/mL). While evaluating the inhibition of fungal germination activities, S. vernalis extract (at a concentration of 0.09 mg/mL) was found to be the most effective against C. albicans ATCC 90028 strain. The results also indicated that S. vernalis extracts at sub-MIC levels inhibited germ tube formation and modulated the tail-length of germinated cells, both of which are important virulence factors of C. albicans. Furthermore, the inhibition of biofilm-formation was also investigated, and it was found that two Sternbergia spp. extracts at or below MIC levels inhibited biofilm formation.

Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors.

Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4a⁻f, potential Michael acceptors, and their reduced analogues succindiamides 5a⁻f were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate (1a) or mono-methyl succinate (1b), hydrolysis of PQ-dicarboxylic acid mono-ester conjugates 2a,b to corresponding acids 3a,b, and a coupling reaction with halogenanilines. 1-[bis(Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) was used as a coupling reagent along with Hünig's base. Compounds 4 and 5 were evaluated against a panel of bacteria, several Mycobacterium strains, fungi, a set of viruses, and nine different human tumor cell lines. p-Chlorofumardiamide 4d showed significant activity against Staphylococcus aureus,Streptococcus pneumoniae and Acinetobacter baumannii, but also against Candida albicans (minimum inhibitory concentration (MIC) 6.1⁻12.5 µg/mL). Together with p-fluoro and p-CF3 fumardiamides 4b,f, compound 4d showed activity against Mycobacterium marinum and 4b,f against M. tuberculosis. In biofilm eradication assay, most of the bacteria, particularly S. aureus, showed susceptibility to fumardiamides. m-CF3 and m-chloroaniline fumardiamides 4e and 4c showed significant antiviral activity against reovirus-1, sindbis virus and Punta Toro virus (EC50 = 3.1⁻5.5 µM), while 4e was active against coxsackie virus B4 (EC50 = 3.1 µM). m-Fluoro derivative 4a exerted significant cytostatic activity (IC50 = 5.7⁻31.2 µM). Acute lymphoblastic leukemia cells were highly susceptible towards m-substituted derivatives 4a,c,e (IC50 = 6.7⁻8.9 µM). Biological evaluations revealed that fumardiamides 4 were more active than succindiamides 5 indicating importance of Michael conjugated system.

Insights into biological activity of ureidoamides with primaquine and amino acid moieties.

Primaquine (PQ) ureidoamides 5a-f were screened for antimicrobial, biofilm eradication and antioxidative activities. Susceptibility of the tested microbial species towards tested compounds showed species- and compound-dependent activity. N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-4-methylpentanamide (5a) and 2-(4-chlorophenyl)-N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]acetamide (5d) showed antibacterial activity against S. aureus strains (MIC = 6.5 µg/ml). Further, compounds 5c and 5d had weak antibacterial activity against Escherichia coli and Pseudomonas aeruginosa. None of the tested compounds showed a wide spectrum of antifungal activity. In contrast, most of the compounds exerted strong activity in a biofilm eradication assay against E. coli, P. aeruginosa and Candida albicans, comparable to or even higher than gentamycin, amphotericin B or parent PQ. The most active compounds were 5a and 5b. Tested compounds were inactive against biofilm formation by C. parapsylosis, Enterococcus faecalis, C. tropicalis and C. krusei. Compounds 5b-f significantly inhibited lipid peroxidation (80-99%), whereas compound 5c presented interesting LOX inhibition.