BACKGROUND AND PURPOSE: Many new compounds are being prepared to overcome the problem of increasing microbial resistance and the increasing number of infections. EXPERIMENTAL APPROACH: This study includes a series of twenty-seven mono-, di- and trisubstituted 2-hydroxynaphthalene-1-carboxanilides designed as multitarget agents. The compounds are substituted with methoxy, methyl, and nitro groups, as well as additionally with chlorine, bromine, and trifluoromethyl at various positions. All the compounds were evaluated for antibacterial activities against Gram-positive and Gram-negative bacteria and mycobacteria. Cytotoxicity on human cells was also tested. KEY RESULTS: Three compounds showed activity comparable to clinically used drugs. N-(3,5-Dimethylphenyl)-2-hydroxynaphthalene-1-carboxamide (13) showed only antistaphylococcal activity (minimum inhibitory concentration (MIC) = 54.9 μM); 2-hydroxy-N-[2-methyl-5-(trifluoromethyl)phenyl]naphthalene-1-carboxamide (22) and 2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]naphthalene-1-carboxamide (27) were active across the entire spectrum of tested bacteria/mycobacteria, both against the sensitive set and against resistant isolates (MICs range 0.3 to 92.6 μM). Compound 22 was even active against E. coli (MIC = 23.2 μM). The active agents showed no in vitro cytotoxicity up to a concentration of 30 μM. CONCLUSION: Compounds with trifluoromethyl in the meta-anilide position, experimental lipophilicity expressed as log k (logarithm of the capacity factor) in the range of 0.31 to 0.34 and calculated electron σ parameter for the anilide substituent higher than 0.59 were effective. The investigated compounds meet the definition of Michael acceptors. Based on ADME screening, the investigated compounds 13, 22 and 27 should have suitable physicochemical parameters for good bioavailability in the organism. Therefore, these are promising agents for further study.

• Keywords
• Lipophilicity, antibacterial activity, antimycobacterial activity, cytotoxicity,
• Publication type
• Journal Article MeSH

A series of thirty-two anilides of 3-(trifluoromethyl)cinnamic acid (series 1) and 4-(trifluoromethyl)cinnamic acid (series 2) was prepared by microwave-assisted synthesis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. (2E)-3-[3-(Trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]prop-2-enamide (1j), (2E)-N-(3,5-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enamide (1o) and (2E)-N-[3-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)-phenyl]prop-2-enamide (2i), (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]-prop-2-enamide (2p) showed antistaphylococcal (MICs/MBCs 0.15-5.57 µM) as well as anti-enterococcal (MICs/MBCs 2.34-44.5 µM) activity. The growth of M. marinum was strongly inhibited by compounds 1j and 2p in a MIC range from 0.29 to 2.34 µM, while all the agents of series 1 showed activity against M. smegnatis (MICs ranged from 9.36 to 51.7 µM). The performed docking study demonstrated the ability of the compounds to bind to the active site of the mycobacterial enzyme InhA. The compounds had a significant effect on the inhibition of bacterial respiration, as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity but also bactericidal activity. Preliminary in vitro cytotoxicity screening was assessed using the human monocytic leukemia cell line THP-1 and, except for compound 2p, all effective agents did show insignificant cytotoxic effect. Compound 2p is an interesting anti-invasive agent with dual (cytotoxic and antibacterial) activity, while compounds 1j and 1o are the most interesting purely antibacterial compounds within the prepared molecules.

• Keywords
• Michael acceptors, antimicrobial activity, cinnamamides, cytotoxicity, docking study, lipophilicity, structure–activity relationships,
• MeSH
• Anti-Bacterial Agents pharmacology   chemistry   MeSH
• Cinnamates pharmacology   chemistry   MeSH
• Humans MeSH
• Methicillin-Resistant Staphylococcus aureus * MeSH
• Microbial Sensitivity Tests MeSH
• Staphylococcal Infections * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Cinnamates MeSH
• cinnamic acid MeSH Browser

Due to the urgent need of innovation in the antimalarial therapeutic arsenal, a series of thirty-seven ring-substituted N-arylcinnamanilides prepared by microwave-assisted synthesis were subjected to primary screening against the chloroquine-sensitive strain of P. falciparum 3D7/MRA-102. The lipophilicity of all compounds was experimentally determined as the logarithm of the capacity factor k, and these data were subsequently used in the discussion of structure-activity relationships. Among the screened compounds, fourteen derivatives exhibited IC50 from 0.58 to 31 µM, whereas (2E)-N-(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide (24) was the most effective agent (IC50 = 0.58 µM). In addition, (2E)-N-[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide (36), (2E)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide (18), (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide (23), and (2E)-3-phenyl-N-(3,4,5-trichlorophenyl)prop-2-enamide (33) demonstrated efficacy in the IC50 range from 2.0 to 4.3 µM, comparable to the clinically used standard chloroquine. The results of a cell viability screening performed using THP1-Blue™ NF-κB cells showed that none of these highly active compounds displayed any significant cytotoxic effect up to 20 μM, which makes them promising Plasmodium selective substances for further investigations.

• Keywords
• Plasmodium, antiplasmodial activity, cinnamanilides, structure-activity relationships,
• MeSH
• Folic Acid Antagonists * MeSH
• Antimalarials * pharmacology   MeSH
• Chloroquine pharmacology   MeSH
• Humans MeSH
• Malaria, Falciparum * MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Folic Acid Antagonists * MeSH
• Antimalarials * MeSH
• Chloroquine MeSH

A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.

• Keywords
• antimicrobial activity, cinnamamides, cytotoxicity, lipophilicity, structure-activity relationships,
• MeSH
• Ampicillin pharmacology   MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Methicillin-Resistant Staphylococcus aureus * MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium tuberculosis * MeSH
• Swine MeSH
• Mammals MeSH
• Staphylococcal Infections * MeSH
• Staphylococcus aureus MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ampicillin MeSH
• Anti-Bacterial Agents MeSH

A series of twenty-two novel N-(disubstituted-phenyl)-3-hydroxynaphthalene- 2-carboxamide derivatives was synthesized and characterized as potential antimicrobial agents. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxy- naphthalene-2-carboxamide showed submicromolar (MICs 0.16-0.68 µM) activity against methicillin-resistant Staphylococcus aureus isolates. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[4-bromo-3-(trifluoromethyl)phenyl]-3-hydroxynaphthalene-2-carboxamide revealed activity against M. tuberculosis (both MICs 10 µM) comparable with that of rifampicin. Synergistic activity was observed for the combinations of ciprofloxacin with N-[4-bromo-3-(trifluoromethyl)phenyl]- and N-(4-bromo-3-fluorophenyl)-3-hydroxynaphthalene-2-carboxamides against MRSA SA 630 isolate. The similarity-related property space assessment for the congeneric series of structurally related carboxamide derivatives was performed using the principal component analysis. Interestingly, different distribution of mono-halogenated carboxamide derivatives with the -CF3 substituent is accompanied by the increased activity profile. A symmetric matrix of Tanimoto coefficients indicated the structural dissimilarities of dichloro- and dimetoxy-substituted isomers from the remaining ones. Moreover, the quantitative sampling of similarity-related activity landscape provided a subtle picture of favorable and disallowed structural modifications that are valid for determining activity cliffs. Finally, the advanced method of neural network quantitative SAR was engaged to illustrate the key 3D steric/electronic/lipophilic features of the ligand-site composition by the systematic probing of the functional group.

• Keywords
• CoMSA, IVE-PLS, MIC, MTT assay, antistaphylococcal activity, antitubercular activity, hydroxynaphthalenecarboxamides, lipophilicity, similarity-activity landscape index,
• MeSH
• Anti-Infective Agents chemical synthesis   MeSH
• Methicillin-Resistant Staphylococcus aureus * MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium tuberculosis * MeSH
• Naphthalenes chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Infective Agents MeSH
• Naphthalenes MeSH
• naphthalene-2-carboxamide MeSH Browser

Ring-substituted 1-hydroxynaphthalene-2-carboxanilides were previously investigated for their antimycobacterial properties. In our study, we have shown their antiproliferative and cell death-inducing effects in cancer cell lines. Cell proliferation and viability were assessed by WST-1 assay and a dye exclusion test, respectively. Cell cycle distribution, phosphatidylserine externalization, levels of reactive oxygen or nitrogen species (RONS), mitochondrial membrane depolarization, and release of cytochrome c were estimated by flow cytometry. Levels of regulatory proteins were determined by Western blotting. Our data suggest that the ability to inhibit the proliferation of THP-1 or MCF-7 cells might be referred to meta- or para-substituted derivatives with electron-withdrawing groups -F, -Br, or -CF3 at anilide moiety. This effect was accompanied by accumulation of cells in G1 phase. Compound 10 also induced apoptosis in THP-1 cells in association with a loss of mitochondrial membrane potential and production of mitochondrial superoxide. Our study provides a new insight into the action of salicylanilide derivatives, hydroxynaphthalene carboxamides, in cancer cells. Thus, their structure merits further investigation as a model moiety of new small-molecule compounds with potential anticancer properties.

• Keywords
• antiproliferative effect, apoptosis, cell cycle, hydroxynaphthalene carboxamides, salicylanilides,
• MeSH
• Anilides chemistry   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• MCF-7 Cells MeSH
• Mitochondria drug effects   metabolism   MeSH
• Molecular Structure MeSH
• Naphthols chemistry   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Salicylanilides chemistry   pharmacology   MeSH
• Superoxides metabolism   MeSH
• THP-1 Cells MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anilides MeSH
• Naphthols MeSH
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH
• salicylanilide MeSH Browser
• Salicylanilides MeSH
• Superoxides MeSH

1-[2-[({[2-/3-(Alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium/azepan- ium oxalates or dichlorides (alkoxy = butoxy to heptyloxy) were recently described as very promising antimycobacterial agents. These compounds were tested in vitro against Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 (reference and control strains), three methicillin-resistant isolates of S. aureus, and three isolates of vancomycin-resistant E. faecalis. 1-[3-(Dipropylammonio)-2-({[3-(pentyloxy-/hexyloxy-/heptyloxy)phenyl]carbamoyl}oxy)propyl]pyrrolidinium dichlorides showed high activity against staphylococci and enterococci comparable with or higher than that of used controls (clinically used antibiotics and antiseptics). The screening of the cytotoxicity of the compounds as well as the used controls was performed using human monocytic leukemia cells. IC50 values of the most effective compounds ranged from ca. 3.5 to 6.3 µM, thus, it can be stated that the antimicrobial effect is closely connected with their cytotoxicity. The antibacterial activity is based on the surface activity of the compounds that are influenced by the length of their alkoxy side chain, the size of the azacyclic system, and hydro-lipophilic properties, as proven by in vitro experiments and chemometric principal component analyses. Synergistic studies showed the increased activity of oxacillin, gentamicin, and vancomycin, which could be explained by the direct activity of the compounds against the bacterial cell wall. All these compounds demonstrate excellent antibiofilm activity, when they inhibit and disrupt the biofilm of S. aureus in concentrations close to minimum inhibitory concentrations against planktonic cells. Expected interactions of the compounds with the cytoplasmic membrane are proven by in vitro crystal violet uptake assays.

• Keywords
• antibacterial, antibiofilm activity, carbamate, structure–activity relationships, synergy,
• Publication type
• Journal Article MeSH

A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure-activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity-activity landscape index for BChE inhibitory response values. The 'indirect' ligand-based and 'direct' protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an 'average' 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).

• Keywords
• CoMSA, IVE-PLS, in vitro cholinesterase inhibition, molecular docking, silicon-based carbamates, similarity-activity landscape index,
• MeSH
• Butyrylcholinesterase MeSH
• Chloroplasts MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Photosystem II Protein Complex MeSH
• Inhibitory Concentration 50 MeSH
• Carbamates chemistry   pharmacology   MeSH
• Silicon chemistry   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Docking Simulation MeSH
• Spinacia oleracea MeSH
• THP-1 Cells drug effects   MeSH
• Electron Transport drug effects   MeSH
• Binding Sites MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Photosystem II Protein Complex MeSH
• Carbamates MeSH
• Silicon MeSH
• Ligands MeSH

A series of twenty-six methoxylated and methylated N-aryl-1-hydroxynaphthalene- 2-carboxanilides was prepared and characterized as potential anti-invasive agents. The molecular structure of N-(2,5-dimethylphenyl)-1-hydroxynaphthalene-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. All the analysed compounds were tested against the reference strain Staphylococcus aureus and three clinical isolates of methicillin-resistant S. aureus as well as against Mycobacterium tuberculosis and M. kansasii. In addition, the inhibitory profile of photosynthetic electron transport in spinach (Spinacia oleracea L.) chloroplasts was specified. In vitro cytotoxicity of the most effective compounds was tested on the human monocytic leukaemia THP-1 cell line. The activities of N-(3,5-dimethylphenyl)-, N-(3-fluoro-5-methoxy-phenyl)- and N-(3,5-dimethoxyphenyl)-1-hydroxynaphthalene-2-carbox- amide were comparable with or even better than the commonly used standards ampicillin and isoniazid. All promising compounds did not show any cytotoxic effect at the concentration >30 µM. Moreover, an in silico evaluation of clogP features was performed for the entire set of the carboxamides using a range of software lipophilicity predictors, and cross-comparison with the experimentally determined lipophilicity (log k), in consensus lipophilicity estimation, was conducted as well. Principal component analysis was employed to illustrate noticeable variations with respect to the molecular lipophilicity (theoretical/experimental) and rule-of-five violations. Additionally, ligand-oriented studies for the assessment of the three-dimensional quantitative structure-activity relationship profile were carried out with the comparative molecular surface analysis to determine electron and/or steric factors that potentially contribute to the biological activities of the investigated compounds.

• Keywords
• 3D-QSAR, CoMSA, MTT assay, PET inhibition, X-Ray structure, antimycobacterial activity, antistaphylococcal activity, cytotoxicity, hydroxynaphthalenecarboxamides, lipophilicity,
• MeSH
• Ampicillin pharmacology   MeSH
• Principal Component Analysis MeSH
• Anilides chemical synthesis   chemistry   pharmacology   MeSH
• Anti-Bacterial Agents chemical synthesis   chemistry   pharmacology   MeSH
• Chloroplasts drug effects   physiology   MeSH
• Photosynthesis drug effects   MeSH
• Isoniazid pharmacology   MeSH
• Humans MeSH
• Methicillin-Resistant Staphylococcus aureus drug effects   growth & development   MeSH
• Methylation MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium kansasii drug effects   growth & development   MeSH
• Mycobacterium tuberculosis drug effects   growth & development   MeSH
• Naphthols chemical synthesis   chemistry   pharmacology   MeSH
• Spinacia oleracea chemistry   drug effects   metabolism   MeSH
• THP-1 Cells MeSH
• Electron Transport drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Ampicillin MeSH
• Anilides MeSH
• Anti-Bacterial Agents MeSH
• Isoniazid MeSH
• Naphthols MeSH

A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fragment-based approach and was synthesized according to the microwave-assisted protocol. The biological activity of all of the compounds was tested on human colon carcinoma cell lines including a deleted TP53 tumor suppressor gene. The mechanism of activity was studied according to the p53 status in the cell. Several compounds revealed a good to excellent activity that was similar to or better than the standard anticancer drugs. Some of these appeared to be more active against the p53 null cells than their wild-type counterparts. Intercalating the properties of these compounds could be responsible for their mechanism of action.

• MeSH
• Apoptosis drug effects   MeSH
• DNA metabolism   MeSH
• Doxorubicin pharmacology   MeSH
• HCT116 Cells MeSH
• Intercalating Agents pharmacology   MeSH
• Small Molecule Libraries chemistry   pharmacology   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Naphthols chemical synthesis   chemistry   pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Drug Design * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-naphthol MeSH Browser
• calf thymus DNA MeSH Browser
• DNA MeSH
• Doxorubicin MeSH
• Intercalating Agents MeSH
• Small Molecule Libraries MeSH
• Tumor Suppressor Protein p53 MeSH
• Naphthols MeSH
• Antineoplastic Agents MeSH