6-Hydroxyquinolinium salts differing in the length of alkyl side-chain: Synthesis and antimicrobial activity

Quaternary ammonium salts substituted with a long alkyl chain exemplify a trustworthy group of medicinal compounds frequently employed as antifungal and antibacterial agents. A great asset of these surfactants underlying their widespread use is low local and system toxicity in humans. In this Letter, a series of novel quaternary 6-hydroxyquinolinium salts with varying length of N-alkyl chain (from C₁₀ to C₁₈) was synthesized and tested for in vitro activity against pathogenic bacterial and fungal strains. 6-Hydroxyquinolinium salt with C12 alkyl chain seems to be very interesting candidate due to a high antimicrobial efficacy and cytotoxic safety.     

Synthesis,molecular docking studies,and antimicrobial evaluation of new structurally diverse ureas

A series of new urea derivatives (3a-p) have been synthesized from readily available isocyanates and amines in good to high yields. All synthesized compounds were fully characterized using ¹H NMR, ¹³C NMR, IR, and mass spectrometry. Additionally, the structure of the compound (3n) was confirmed by single-crystal X-ray diffraction. Furthermore, all compounds were evaluated for antimicrobial activity against five bacteria and two fungi. Last but not the least, molecular docking studies with Candida albicans dihydropteroate synthetase were performed and the results are presented herein.     

New series of fused pyrazolopyridines: Synthesis,molecular modeling,antimicrobial, antiquorum-sensing and antitumor activities

New series of fused pyrazolopyridines were prepared and assessed for antimicrobial, antiquorum-sensing and antitumor activities. Antimicrobial evaluation toward selected Gram-positive bacteria, Gram-negative bacteria and fungi indicated that 5-phenylpyrazolopyridotriazinone 4a has good and broad-spectrum antimicrobial activity. In addition, 5-(4-chlorophenyl)pyrazolopyridotriazinone 4b and 5-(4-(dimethylamino)phenyl)pyrazolopyridotriazinone 4c exhibited good activity against the selected Gram-positive bacteria and A. fumigatus, whereas 5-amino-4-phenylpyrazolopyridopyrimidine 6a demonstrated good activity against B. cereus and P. aeruginosa. Furthermore, 6-amino-5-imino-4-phenylpyrazolopyridopyrimidine 7a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b demonstrated promising activity against the tested Gram-negative bacteria and fungi, and moderate activity against Gram-positive bacteria. Antiquorum-sensing screening over C. violaceum illustrated that 4a, 6a and 7a-c have strong activity. In vitro antiproliferative assessment of the new derivatives against HepG2, HCT-116 and MCF-7 cancer cells revealed that 7a is the most active analog against all tested cell lines. Likewise, 3,7-dimethyl-4-phenylpyrazolopyridopyrimidinone 2a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b manifested strong activity against all examined cell lines. In vivo antitumor testing of 2a, 7a and 7b against EAC cells in mice indicated that 7a has the highest activity. Cytotoxicity toward WI38 and WISH normal cells was also assessed and results assured that all of the investigated analogs have lower cytotoxicity than doxorubicin. DNA-binding affinity and topoisomerase IIβ inhibitory activity were evaluated, and results revealed that 5b, 7a and 7b bind strongly to DNA; in addition, 2a, 4a, 7a and 7b manifested higher topoisomerase IIβ inhibitory activity than that of doxorubicin. Analogs 5b, 7a and 7b were docked into topoisomerase IIβ, and results indicated that 7a and 7b have the highest binding affinity toward topoisomerase IIβ. In silico simulation studies referred that most of the new analogs comply with the optimum needs for good oral absorption. Also, computational carcinogenicity evaluation was predicted.     

Newly synthesized dopamine ester derivatives and assessment of their antioxidant,antimicrobial and hemolytic activities

Preparation of dopamine derivatives was carried out as a response to the increasing demand for new lipophilized antioxidants in food, cosmetic and pharmaceutical industries. A large series of dopamine esters (DA-C₃ to DA-C_18:1) with increasing lipophilicity was synthesized using lipase from Candida antarctica (Novozyme 435) as a biocatalyst. The highest conversion yield (52.75%) was reached when caprylic acid (DA-C₈) was used as acyl donor. Synthesized compounds were purified and evaluated for their antioxidant activity using the DPPH and the ABTS tests. Results showed that esterification had little effect on radical-scavenging capacity. However, long chain fatty acid esters displayed higher protective effect of oil against oxidation at 70 °C as compared to the parent dopamine or to the BHT. The hemolytic activity of dopamine esters was studied. Middle chain length derivatives (DA-C₈ and DA-C₁₂) of dopamine and oleic acid derivative (DA-C_18:1) showed the highest hemolytic activity against human erythrocyte. The antimicrobial activities of dopamine esters were also evaluated using well diffusion and minimal inhibition concentration methods. Among all the tested compounds, DA-C₈ and DA-C₁₂ exhibited the highest antibacterial activities. These results open up potential applications by using dopamine derivatives as antioxidants and antimicrobial compounds in cosmetic, food and pharmaceutical industries.     

Design,synthesis, characterization,antimicrobial evaluation and molecular modeling studies of some dehydroacetic acid-chalcone-1,2,3-triazole hybrids

A series of new dehydroacetic acid chalcone-1,2,3-triazole hybrids as potential antimicrobial agents was designed, synthesized and characterized by FTIR, NMR and HRMS spectral techniques. All the synthesized compounds were screened in vitro against four bacterial strains (Staphylococcus epidermidis, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) and two fungal strains (Aspergillus niger and Candida albicans). The antimicrobial results indicated that some of the compounds showed remarkable activities comparable to the standard drugs. Most of the compounds exhibited better efficacy compared to the DHA, which is itself an antimicrobial agent. The synergistic effect in biological activity was observed when DHA, chalcone and 1,2,3-triazole are conjugated. The molecular modeling studies of compound 5j into E. coli topoisomerase II DNA gyrase B were also performed.     

Synthesis,antimicrobial activity and molecular modeling study of substituted 5-aryl-pyrimido[5,4-c]quinoline-2,4-diones

A series of pyrimido[5,4-c]quinoline-2,4-dione derivatives 5a–k were synthesized in moderate yields via a thermolysis reaction of equimolar ratio of 5-arylidine-1,3-dimethylbarbituric acid derivatives 3a–d with aniline derivatives 4a–d at 150–180 °C for 1–2?h. Eight of the synthesized compounds were chosen for a primary in vitro one-dose anticancer assay performed using the full NCI 60 cell panel. Only compound 5b showed moderate GI% at the used dose (10 μM) against four of the tested cell lines corresponding to leukemia SR (GI%: 51), non small-cell lung cancer HOP-92 (GI%: 63), melanoma UACC-62 (GI%: 53) and renal cancer UO-31 (GI%: 69). On the other hand, antimicrobial screening of the whole set of the synthesized compounds was performed against three Gram +ve and two Gram ?ve bacterial strains. Results of the antimicrobial screening showed that compounds 5d, 5e, 5f, 5h and 5k have broad-spectrum antibacterial efficacy being moderately active against all the tested Gram +ve and two Gram ?ve bacteria. Also, compound 5a showed interesting results being only active against Streptococcus faecalis and both tested Gram ?ve strains viz. E. coli and P. aeruginosa. In order to compare the binding mode of the most active compounds 5e and 5f along with the inactive compound 5c we docked these compounds into the empty binding site of topoisomerase II DNA gyrase (PDB ID: 1KZN), and results were compared with the bound inhibitor Clorobiocin.     

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.     

Synthesis and antimicrobial profile of N-substituted imidazolium oximes and their monoquaternary salts against multidrug resistant bacteria

Two different series of N-substituted imidazolium oximes and their monoquaternary salts were synthesized and biologically tested with respect to their ability to inhibit growth a diverse panel of antibiotic susceptible Gram-positive and antibiotic resistant Gram-negative bacteria as well fungal strains. The newly synthesized compounds were analyzed by spectral studies to confirm their structure. The preliminary results showed that all compounds tested possess promising antimicrobial potential against both susceptible Gram-positive and antibiotic resistant Gram-negative isolates, exhibiting a wide range of MIC values from 0.14 to 100.0 μg/mL. The structure–activity relationship demonstrates that the p-methylphenyl and p-fluorophenyl groups in monoquaternary salts 6 and 7 attached directly to the imidazolium ring could be essential for observed remarkable inhibitory profiles against clinically important pathogens Pseudomonas aeruginosa (MIC = 0.14 μg/mL) and Klebsiella pneumoniae (MIC = 1.56 μg/mL). Furthermore, the broth microdilution assay was then used to investigate the antiresistance efficacy of compound 7 against fourteen extended-spectrum β-lactamase (ESBL)-producing strains in comparison to eight clinically relevant antibiotics. Compound 7 exhibited a remarkable antiresistance profiles ranging between 0.39 and 12.50 μg/mL against all of ESBL-producing strains, which leads to the suggestion that may be interesting candidate for development of new antimicrobials to combat multidrug resistant Gram-negative bacteria.     

Synthesis,biological evaluation and molecular modeling of novel thienopyrimidinone and triazolothienopyrimidinone derivatives as dual anti-inflammatory antimicrobial agents

New thienopyrimidinone and triazolothienopyrimidinone derivatives have been synthesized. These compounds were subjected to anti-inflammatory and antimicrobial activity screening aiming to identify new candidates that have dual anti-inflammatory and antimicrobial activities.Compounds 5, 7 and 10a showed minimal ulcerogenic effect and high selectivity towards human recombinant COX-2 over COX-1 enzyme. Their docking outcome correlated with their biological activity and assured the high selectivity binding towards COX-2. In addition, they could act safely up to 80 mg/kg orally or 40 mg/kg parentrally. The antimicrobial screening showed that compound 10a displayed distinctive inhibitory effect on the growth of Escherichia coli comparable to that of ampicillin. Moreover, compounds 5, 7, 9 and 12a possessed 50% of the inhibitory activity of ampicillin against E. coli. Thus, compounds 5, 7 and 10a represent promising dual acting anti-inflammatory and antimicrobial agents. This work provides rewarding template enriching the chemical space for dual anti-inflammatory anti-microbial activities.     

Synthesis and antimicrobial evaluation of bile acid tridentate conjugates

Two series of novel bile acid tridentate conjugates with different linkers were synthesized and characterized, and their biological activities in vitro were evaluated. The procedure was straightforward and efficient to be carried out with high overall yield. The antimicrobial activity of the synthesized compounds against Saccharomyces cerevisiae, Aspergillus niger, Escherichia coli and Staphylococcus aureus was investigated in vitro. The best activity of minimal inhibitory concentrations (MICs) for 1c, 1c′, 2c and 2c′ against S. cerevisiae was up to 0.125 μg/mL.     

Synthesis,characterization, in vitro cytotoxicity and antimicrobial investigation and evaluation of physicochemical properties of novel 4-(2-methylacetamide)benzenesulfonamide derivatives

In this study, several sulfonamide derivatives, 4-(2-methylacetylamino)benzenesulfonamides were synthesized. Chemical structures of the derivatives were characterized by ¹H NMR, ¹³C NMR, LC–MS–MS, UV–Vis, FTIR, photoluminescence and elemental analysis. Sulfanilamide was reacted with 2-bromopropionyl bromide, in the presence of pyridine, to form bromo-substituted sulfonamide key intermediates, which were subsequently treated with secondary amines to obtain novel sulfonamide derivatives. All the synthesized compounds were evaluated for in vitro antimicrobial activities and cytotoxicity. Increases in ring size, and rings bearing a nitrogen heteroatom led to improvements in antimicrobial activities. As the presence of CA IX and CA XII enzymes have been implicated in some cancerous tumors, the studies presented herein focuses on targeting these enzymes. It was found that the synthesized derivatives had in vitro anti-cancer properties, where compounds (3–6) were found to be active against all cancerous cells, and no cytotoxic effects on normal cells were observed.     

New trifluoromethyl quinolone derivatives: Synthesis and investigation of antimicrobial properties

A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria, three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal activity against Aspergillus fumigatus and Aspergillus flavus.     

Synthesis and antimycobacterial evaluation of N-substituted 5-chloropyrazine-2-carboxamides

To develop new potential antimycobacterial drugs, a series of pyrazinamide derivatives was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial strains (Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two strains of Mycobacterium avium). This Letter is focused on binuclear pyrazinamide analogues containing the –CONH–CH₂– bridge, namely on N-benzyl-5-chloropyrazine-2-carboxamides with various substituents on the phenyl ring and their comparison with some analogously substituted 5-chloro-N-phenylpyrazine-2-carboxamides. Compounds from the N-benzyl series exerted lower antimycobacterial activity against M. tuberculosis H37Rv then corresponding anilides, however comparable with pyrazinamide (12.5–25 μg/mL). Remarkably, 5-chloro-N-(4-methylbenzyl)pyrazine-2-carboxamide (8, MIC = 3.13 μg/mL) and 5-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (1, MIC = 6.25 μg/mL) were active against M. kansasii, which is naturally unsusceptible to PZA. Basic structure–activity relationships are presented.     

Targeting hepatocellular carcinoma: Synthesis of new pyrazole-based derivatives,biological evaluation,DNA binding,and molecular modeling studies

A new series of pyrazole derivatives was prepared in this work, including pyrazolopyrimidines, pyrazolotriazines, pyrazolylthienopyridines, and 2-(pyrazolylamino)thiazol-4-ones, utilizing 3-amino-5-methyl-1H-pyrazole as a synthetic precursor. Their in vitro anticancer activity was tested on hepatocellular carcinoma cell line, HepG2. The results revealed that the pyrazolylhydrazonoyl cyanide 8, the pyrazolopyrimidine 3, and the pyrazolylaminothiazolone 17 were the most active with IC₅₀ values of 2, 7, and 7 µM respectively in comparison with 5.5 µM for cisplatin as a reference drug. Interestingly, all the synthesized compounds showed higher selectivity index than cisplatin. DNA binding assay was also carried out for the synthesized compounds to rationalize their mechanism of action. Molecular modeling studies, including docking into DNA minor groove, flexible alignment, and surface mapping, were conducted. Results obtained proved the superior DNA-binding affinity of the most active anticancer compounds.     

Synthesis,biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors

A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC₅₀ value of 0.01 μM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC₅₀ values of 25.4 and 9.5 μg/ml, respectively. Compounds 15, 20, 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin. Strong activity was observed for 13, 14, 19, 20 and 24 against Candida albicans and Aspergillus flavus. Compound 17 shared a similar molecular docking mode with MTX and made a critical hydrogen bond and arene-arene interactions via Ala9 and Phe34 amino acid residues, respectively.     

Design,synthesis, molecular docking of new lipophilic acetamide derivatives affording potential anticancer and antimicrobial agents

Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33–40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 µM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents.     

Synthesis,biological evaluation and molecular docking studies of a new series of chalcones containing naphthalene moiety as anticancer agents

A series of chalcones containing naphthalene moiety 4a–4p have been synthesized, characterized by ¹H NMR and ¹³C NMR and evaluated for their in vitro anticancer activity. The majority of the screened compounds displayed potent anticancer activity against both HCT116 and HepG2 human cancer cell lines. Among the series, compound 4h with a diethylamino group at the para position of the phenyl ring exhibited the most potent anticancer activity against HCT116 and HepG2 cell lines with IC₅₀ values of 1.20 ± 0.07 and 1.02 ± 0.04 μM, respectively. The preliminary structure–activity relationship has been summarized. Tubulin polymerization experiments indicated that 4h effectively inhibited tubulin polymerization and flow cytometric assay revealed that 4h arrests HepG2 cells at the G2/M phase in a dose-dependent manner. Furthermore, molecular docking studies suggested that 4h binds to the colchicine binding site of tubulin.     

Synthesis,molecular modeling and biological evaluation of new pyrazolo[3,4-b]pyridine analogs as potential antimicrobial,antiquorum-sensing and anticancer agents

New pyrazolo[3,4-b]pyridine analogs 2–9 were synthesized and subjected to antimicrobial testing toward chosen Gram-negative bacteria, Gram-positive bacteria and fungi. Compound 2 exhibited potent and extended-spectrum antimicrobial activity. Further, 6 and 9c demonstrated remarkable and extended-spectrum antibacterial activity. Antiquorum-sensing activity of the new members was tested over C. violaceum, whereas 9c demonstrated strong efficacy, while 2, 8b and 9b displayed moderate efficacy. In vitro anticancer assay toward HepG2, MCF-7 and Hela cancer cells manifested that 2 and 9c are powerful and extended-spectrum anticancer agents. Additionally, 8a, 8b and 9b showed excellent activity toward the three cancer cells. In vivo anticancer assay over EAC in mice indicated that 2 and 9c have the greatest activity. Moreover, cytotoxicity assay over WISH and W138 normal cells clarified that the checked analogs possess weak cytotoxicity toward the two normal cells. DNA-binding affinity was also tested, whereas 2, 3, 8b, 9b and 9c demonstrated great affinity. Molecular modeling studies revealed that the investigated compounds bind to DNA through intercalation similarly to doxorubicin. In silico studies revealed that the new members are anticipated to show excellent intestinal absorption.     

Synthesis,physiochemical property and antimicrobial activity of novel quaternary ammonium salts

Twenty-four novel 5-phenyl-1,3,4-oxadiazole-2-thiol (POT) analogues, benzo[d]oxazole-2-thiol, benzo[d]thiazole-2-thiol and 5-methyl-1,3,4-thiadiazole-2-thiol-substituted N,N-bis(2-hydroxyethyl) quaternary ammonium salts (QAS) (5a-d, 6a-d, 7a-d, 10a-d, 13a-d, 16a-d) were prepared and characterised by FTIR, NMR and elemental analysis. Part of target compounds (5d, 6d, 7d, 10d, 13d, 16d) displayed potent antimicrobial effect against ten common pathogens (S. aureus, α-H-tococcus, β-H-tococcus, E. coli, P. aeruginosa, Proteus vulgaris, Canidia Albicans, Cytospora mandshurica, Physalospora piricola, Aspergillus niger) and had relatively low cytotoxity against two human cell lines (HaCat and LO2). TEM and SEM images of E. coli and S. aureus morphologies treated with 7d showed that the antibacterial mechanism might be the QAS fixing on cell wall surfaces and puncturing to result in the release of bacterial cytoplasm. This study provides new information of QAS, which could be used to design novel antimicrobial agents applied in clinic or agriculture.