Antibacterial,antifungal and cytotoxic properties of some sulfonamide-derived chromones

A series of antibacterial and antifungal sulfonamide (sulfanilamide, sulfaguanidine, sulfamethaxozole, 4-aminoethylbenzenesulfonamide and 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide) derived chromones, previously reported as inhibitors of carbonic anhydrase, have been screened for in-vitro antibacterial activity against four Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Shigella flexeneri) and two Gram-positive (Bacillus subtilis and Staphylococcus aureus) bacterial strains, and for in-vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, Candida glaberata. All compounds (1)–(5) showed significant antibacterial activity against all four Gram-negative species and both Gram-positive species. However, three of them, (1), (4) and (5), were found to be comparatively much more active compared to (2) and (3). Of these, (5) was found to be the most active one. For antifungal activity, generally compounds (1) and (2) showed significant activity against more than three strains whereas (3)–(5) also showed significant activity against varied fungal strains. In the brine shrimp bioassay for in-vitro cytotoxic properties, only two compounds, (4) and (5) displayed potent cytotoxic activity, LD₅₀ = 2.732 × 10^{? 4} M) and LD₅₀ = 2.290 × 10^{? 4} M) respectively, against Artemia salina.     

First Synthesis of Double Headed 1,3,4‐Oxadiazino[6,5‐b]indole Acyclo C‐Nucleosides

Condensation of 1,3‐dihydro‐2,3‐dioxo‐2H‐indoles (1a–c) with galactaric acid bis hydrazide (2) gave the corresponding galactaric acid bis[2‐(1,2‐dihydro‐2‐oxo‐3H‐indol‐3‐ylidene)hydrazides] (3a–c). Acetylation of the latter compounds with acetic anhydride in the presence of pyridine at ambient temperature gave the 2,3,4,5‐tetra‐O‐acetylgalactaric acid bis[2‐(1,2‐dihydro‐2‐oxo‐1‐substituted‐3H‐indol‐3‐ylidene)hydrazides] (4b–d). Heterocyclization of the tetra‐O‐acetates 4b–d by heating with thionyl chloride afforded the double headed acyclo C‐nucleosides: 1,2,3,4‐tetra‐O‐acetyl‐1,4‐bis{9‐substituted‐1,3,4‐oxadiazino[6,5‐b]indol‐2‐yl‐1‐ium}‐galacto‐tetritol dichlorides (5b–d). Structures of the prepared compounds were elucidated from their spectral properties.     

Design,synthesis and evaluation of some 1,3,5-triazinyl urea and thiourea derivatives as antimicrobial agents

In an effort to establish new candidates with improved antimicrobial activities we report here the synthesis and in vitro biological evaluation of various series of compounds (5a-j) and (7a-j) which were evaluated against two Gram positive (S. aureus, B. subtilis), two Gram negative (S. typhosa, E. coli) strains and a yeast-like fungi (C. albicans) using the micro-dilution procedure. Among the synthesized compounds 2-(cyclohexyl amino)-4-(3,4-dimethoxy phenyl ethyl thioureido)-6-(2-chloro phenyl ureido) s-triazine (7e) and 2-(cyclohexyl amino)-4-(3,4-dimethoxy phenyl ethyl thioureido)-6-(4-chloro phenyl ureido) s-triazine (7g) proved to be effective with MIC (0.019 mg ML^?1) against S. typhosa & E. coli respectively.     

Microwave-Assisted Synthesis of 2(1H)-Pyridones and Their Glucosides as Cell Proliferation Inhibitors

A new series of substituted 2(1H)-pyridones (4a–i) and their glucosides (5, 6a–e) were prepared as potential agents against leukemia (HL-60) cells. Glucosides (5,6a–e) were synthesized using three independent methods. Microwave protocol as an ecologically new method was used to synthesize the target compounds. Structures of the new products were confirmed using one- and two-dimensional NMR spectroscopy. In vitro exposure of pyridones substituted at position 4 with a 2-thienyl or 2-(trifluoromethyl)phenyl were found to exhibit high antiproliferation activities; in particular, 3-cyano-4-(thien-2′-yl)-6-(4″-chlorophenyl)-2(1H)-pyridone (4c) and its glucoside analogue (6c) had the highest activity.     

Structure and Hypotensive Effect of Flavonoid Glycosides in Kinkan (Fortunella japonica) Peelings

An attempt was made to isolate the hypotensive substances from a hot water extract of kinkan. Eight flavonoid glycosides were isolated by repeated chromatography and by gel filtration after extracting with n-butanol and treating with lead subacetate. Their structures were established to be 6,8-di-C-glucosylapigenin (1), 3,6-di-C-glucosylacacetin (2), 2″-O-α-l-rhamnosyl-4′-O-methyl-vitexin (3), 2″-O-α-l-rhamnosyl-4′-O-methylisovitexin (4), 2″-O-α-l-rhamnosylvitexin (5), 2″-O-α-l-rhamnosylorientin (6), 2″-O-α-l-rhamnosyl-4′-O-methylorientin (7) and ponicilin (8) by UV. MS, ¹-NMR and ¹³C-NMR spectroscopy, and by sugar analysis. Each component was intravenously injected in SHR-SP (0.5 ~ 1.0 mg/100 g of body weight), 1, 2, 5 and 6 were found to lower the rat blood pressure.

Among these compounds, 2, 3, 4, 6 and 7 were new flavone glycosides.     

Design,synthesis and pharmacological evaluation of novel tetrasubstituted thiophene analogues as anti-inflammatory agents

A new series of tetrasubstituted thiophene analogues (4a-4f, 5a-5f and 8a-8i) were designed incorporating the pharmacophoric features of COX-1 (as in fenamates), 5-LOX and the p38 MAP kinase inhibitors. The designed series was synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2) yielding the addition product l-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3/7); which on reaction with substituted phenacyl bromides gave the targeted tetrasubstituted thiophene esters (4a-4f / 8a-8i). The tetrasubstituted thiophenes esters (4a-4f ) on hydrolysis with one equivalent of potassium hydroxide solution in methanol at room temperature gave corresponding acids (5a-5f ). All the targeted compounds were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40 mg/kg body weight using standard drugs mefanamic acid and ibuprofen. The compounds (4c, 4e, 4f, 5f, 8a- 8i) which gave reasonable protection to the inflamed paw, eliciting good or moderate comparable anti-inflammatory activity were selected for investigating their analgesic activity using acetic acid induced writhing response test in albino mice at 10 mg/kg dose using standard drug ibuprofen and in order to arrive at possible mechanism of their anti-inflammatory activity, in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL were performed using standard drug ascorbic acid.     

Evaluation of natural antioxidants of Leuzea carthamoides as a result of a screening study of 88 plant extracts from the European Asteraceae and Cichoriaceae

In recently, there has been a great interest in natural antioxidants as bioactive components of food, nutraceuticals or potential drugs against several diseases. In our study, 88 extracts from various parts of plants from European Asteraceae and Cichoriaceae were assayed for radical scavenging activity by means of DPPH (1,1-diphenyl-2-picryl hydrazyl radical) test using the SIA (Sequential injection analysis) method developed for this purpose in our laboratory. DPPH radical scavenging activity of all tested plant extracts was evaluated according to the IC₅₀ parameter. 29 extracts exhibited IC₅₀ value lower than 0.1 mg/mL. The leaves of Leuzea carthamoides (IC₅₀ = 0.046 mg/mL) were chosen as the most promising sample for a subsequent phytochemical study, which resulted in isolation of seven natural compounds, namely, 4′,5,7-trihydroxy-6-methoxyflavone (hispidulin) (1), 5, 7, 3′, 4′- tetrahydroxyflavanone (eriodictyol) (2), 3′,4′,5,7-pentahydroxy-6-methoxyflavonol (patuletin) (3), eriodictyol-7-β-glucopyranoside (4), 6-hydroxykaempferol-7-O-(6″-O-acetyl-β-D-glucopyranoside) (5), 4-hydroxybenzoic acid (6) and 3,4-dihydroxybenzoic acid (protocatechuic acid) (7). Antioxidant activity of the isolated compounds was evaluated by DPPH test and ferric reducing antioxidant power (FRAP) test and compared with trolox and quercetin. Both tests evaluated the flavonoid (5) as the most active antioxidant. This result was confirmed by comparison with known data concerning the structure/activity relationships of flavonoids.     

Metal-based ethanolamine-derived compounds: a note on their synthesis,characterization and bioactivity

Abstract

Metal-based ethanolamines, (L¹)–(L⁴) coordinated with Co(II), Cu(II), Ni(II) and Zn(II) metals in 1:2 (metal:ligand) molar ratio to produce new compounds have been reported. These compounds were screened for their bactericidal/fungicidal activity against a number of bacterial (Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa, Salmonella typhi, Staphylococcus aureus and Bacillus subtilis) and fungal strains (Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata) alongside against a shrimp species known as Artemia salina. The screening results indicated that metal complexes have significantly higher activity than uncomplexed ligands against one or more bacterial/fungal species due to chelation. The ligand (L⁴) displayed good bacterial and fungal activity as compared to other ligands. The antibacterial results revealed that the Zn(II) complex (16) of (L⁴) was found to be the most active complex and Co(II) complex (14) of the same ligand (L⁴), demonstrated the highest antifungal activity.     

Synthesis,antimicrobial and antiviral activity of substituted benzimidazoles

In the present study we have synthesized (4-nitrophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanones, (2-bromophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanone analogues (1–14) and evaluated them for their antimicrobial and antiviral potential. The results of antimicrobial screening indicated that none of the synthesized compounds were effective against the tested bacterial strains. Compounds 3, 11, 13 and compounds 5, 11, 12 were found to be active against Aspergillus niger and Candida albicans respectively, and may be further developed as antifungal agents. Furthermore, evaluation against a panel of different viruses pointed out the selective activity of compounds 5 and 6 against vaccinia virus and Coxsackie virus B4.     

Synthesis,in vitro antitumour activity,and molecular docking study of novel 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinone analogues

A novel series of 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinones 1–20 was synthesised and evaluated for in vitro antitumour activity. N-(4-Chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)acetamide (7) and N-(3,4,5 trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide (19) exhibited excellent antitumour properties, with mean growth inhibitory concentration (GI₅₀) of 17.90 and 6.33 µΜ, respectively, compared with those of 5-fluorouracil 5-FU, gefitinib, and erlotinib (mean GI₅₀: 18.60, 3.24, and 7.29 µΜ, respectively). Comparison of the GI₅₀ (µM) values of compounds 7 and 19 versus those of 5-FU, gefitinib, and erlotinib against an in vitro subpanel of tumour cells lines showed that compounds 7 and 19 have activities almost equal to or higher than that of those standard drugs, especially against lung, CNS, and breast cancer cells. However, compounds 5, 10, 14, 15, 16, 17, and 20 exhibited effective antitumour activity against the different cell lines tested, with growth inhibition percentage (MGI%) of 19, 24, 19, 17, 16, 15, and 16, respectively. A modelling study was performed for compounds 7 and 19 by docking them into the EGFR kinase enzyme to study their mode of binding with the putative binding site.     

Synthesis and Anti-juvenile Hormone Activity of 1-Citronellyl-5-substituted Imidazoles

A number of 1-citronellyl-5-substituted imidazoles were synthesized and bioassayed on the silkworm, Bombyx mori, in order to assess their anti-juvenile hormone activity. Most of the 1-citronellyl-5-substituted imidazoles induced precocious metamorphosis in the 3rd and 4th instar larvae of B. mori by topical application. The percentage of precocious metamorphosis correlated well with the dosage. Among the compounds tested, l-citronellyl-5-(2-chlorophenyl)imidazole (8) and the 2-methylphenyl analog 10 showed the highest activity. When compounds 8 and 10 were applied to the 4th instar larvae at 10 μg/larva, precocious pupation was induced in 100% without any lethal effects.     

Highly Stereoselective Synthesis and Biological Properties of Nucleoside Analogues Bearing a Spiro Inserted Oxirane Ring

Abstract

Starting from 2′,5′-di-O-TBDMS-3′-ketouridine 1 or its thymine analogue 2, both xylo (3–10) and ribo (20) epimers of a series of 3″-substituted 3′-spironucleosides have been obtained in good yields and with a total stereoselectivity. Most new compounds were moderately cytotoxic with in some cases slightly selective antiproliferative activities. None of these compounds was active against HIV, but some other antiviral activities against HSV-2, CMV, EBV, or VZV, in the micromolar range, were noted in specific cases.     

Synthesis of a novel class of some 1,3,4-oxadiazole derivatives as antimicrobial agents

In an effort to discover new candidates with improved antimicrobial activities we report here the synthesis and in vitro biological evaluation of various series of 2-{(3,4,5-trimethoxy phenyl-1,3,4-oxadiazolyl)-5-thio}-4-(morpholino)-6-(phenyl ureido)-s-triazine (7a-i) and 2-{(3,4,5-trimethoxy phenyl-1,3,4-oxadiazolyl)-5-thio}-4-(morpholino)-6-(phenyl thioureido)-s-triazine (8a-g). Antimicrobial properties of the title compounds were investigated against two Gram ( + ve) bacteria (S. aureus, B. subtilis), two Gram ( ? ve) bacteria (P. aeruginosa, E. coli) and yeast-like fungi (C. albicans) using the broth microdilution method.     

Biotransformation of artemisinic acid by the fungus Trichothecium roseum and anti-candidal activity of its metabolites

The microbial transformation of artemisinic acid (1) using cell culture of endophytic fungus Trichothecium roseum was investigated. Previously, we have reported two major metabolites, 3β-hydroxyartemisinic acid (2) and 3β,15-dihydroxyartemisinic acid (3) from the biotransformation of artemisinic acid by the fungus T. roseum CIMAPN1. Here in the present paper, we obtained a new minor compound 4 (5.2% in yield) along with compounds 2 and 3 through scale-up of biotransformation process of artemisinic acid using the same fungus. The structure of compound 4 was established as 3-oxoartemisinic acid on the basis of its IR, ESI-MS, HRMS, 1?D (¹H and ¹³C, DEPT), and 2?D (COSY, HSQC, HMBC) NMR spectral data analysis. The possible reaction mechanism of the formation of 3-oxoartemisinic acid from artemisinic acid was proposed. Furthermore, all the three metabolites along with the artemisinic acid were evaluated for their antifungal activity against the three fungal strains Candida albicans (ATCC 14053), Candida albicans clinical isolates and Candida kefyr (ATCC 204093). 3-Oxoartemisinic acid was the most active (4 to 16 times more potent than artemisinic acid) with MIC ranges from 125 to 500?µg/mL among all tested compounds. This study suggested that the artemisinic acid molecule has a great potential to be exploited for further biotransformation by the different fungi and can produce chemically diverse molecules with better biological activity.     

Metal-based sulfonamides: Their preparation,characterization and in-vitro antibacterial,antifungal & cytotoxic properties. X-ray structure of 4-[(2-hydroxybenzylidene) amino] benzenesulfonamide

Synthesis, characterization and biological studies of Schiff base-derived sulfonamides and their Co (II), Cu (II), Ni (II) and Zn (II) complexes have been reported and screened for in-vitro antibacterial activity against six Gram-negative; E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, S. typhi and S. dysenteriae and four Gram-positive; B. cereus, C. diphtheriae, S. aureus and S. pyogenes bacterial strains and for in-vitro antifungal activity against T. longifusus, C. albicans, A. flavus, M. canis, F. solani, and C. glaberata. All compounds showed moderate to significant antibacterial activity, however, the zinc (II) complexes were found to be more active. Some of the compounds also showed significant antifungal activity against various fungal strains. Only compounds (6) and (10) displayed potent cytotoxic activity with LD₅₀ = 4.644 × 10^{? 4} and 4.106 × 10^{? 4} moles/mL respectively, against Artemia salina. The X-ray structure of 4-[(2-hydroxybenzylidene)amino]benzenesulfonamide is also reported.     

Design,synthesis and pharmacological evaluation of novel azole derivatives of aryl acetic acid as anti-inflammatory and analgesic agents

A series of substituted azole derivatives (3a–e, 4a–e and 5a–e) were synthesised by the cyclisation of N¹(diphenylethanoyl)-N⁴-substituted phenyl thiosemicarbazides under various reaction conditions. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen, were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds 5-(diphenylmethyl)-N-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3b) and 5-(diphenylmethyl)-N-(3-chloro-4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3c) emerged as the most active compounds of the series, and were moderately more potent than the standard drug, ibuprofen. (This abstract was published in Inflammation Research, Supplement 2, Volume 56, page A101, 2008.)     

Plant growth regulators and Axl and immune checkpoint inhibitors from the edible mushroom Leucopaxillus giganteus

ABSTRACT

A novel compound, (R)-4-ethoxy-2-hydroxy-4-oxobutanoic acid (1), and six known compounds (2–7) were isolated from the fruiting bodies of the wild edible mushroom Leucopaxillus giganteus. The planar structure of 1 was determined by the interpretation of spectroscopic data analysis. The absolute configuration of 1 was determined by comparing specific rotation of the synthetic compounds. In the plant regulatory assay, the isolated compounds (1–7) and the chemically prepared compounds (8–10) were evaluated their biological activity against the lettuce (Lactuca sativa) growth. Compounds 1 and 3–10 showed the significant regulatory activity of lettuce growth. 1 showed the strongest inhibition activity among the all the compounds tested. In the lung cancer assay, all the compounds were assessed the mRNA expression of Axl and immune checkpoints (PD-L1, PD-L2) in the human A549 alveolar epithelial cell line by RT-PCR. Compounds 1–10 showed significant inhibition activity against Axl and/or immune checkpoint.     

Synthesis and Antiviral Activity of C-5 Substituted Analogues of D4T Bearing Methylamino- or Methyldiamino-Linker Arms

Abstract

A general strategy is reported for the preparation of C-5-methylamino- or methyldiamino-d4T analogues of “different sizes”. Reactions of the 2′,3′-didehydro-2′,3′-dideoxy-C-5 hydroxymethyl precursor (7) with either polymethylene diamines (n = 6, 8, 10 and 12) or propargylamine proceed regioselectively via subtitution reactions at the C-5 position of uracil. The compounds were evaluated for antiviral activity and cytotoxicity. No significant activity was observed for compounds 9, 11, and 13, but 10 and 12 exhibited a weak activity against HIV-1.     

Study of reactivity of cyanoacetohydrazonoethyl-N-ethyl-N-methyl benzenesulfonamide: preparation of novel anticancer and antimicrobial active heterocyclic benzenesulfonamide derivatives and their molecular docking against dihydrofolate reductase

Abstract

This article describes the synthesis of some novel heterocyclic sulfonamides having biologically active thiophene 3, 4, 5, 6, coumarin 8, benzocoumarin 9, thiazole 7, piperidine 10, pyrrolidine 11, pyrazole 14 and pyridine 12, 13. Starting with 4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)-N-ethyl-N-methylbenzenesulfonamide (2), which was prepared from condensation of acetophenone derivative 1 with 2-cyanoacetohydrazide. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR and MS spectral data. All the newly synthesized heterocyclic sulfonamides were evaluated as in-vitro anti-breast cancer cell line (MCF7) and as in-vitro antimicrobial agents. Compounds 8, 5 and 11 were more active than MTX reference drug and compounds 12, 7, 4, 14, 5 and 8 were highly potent against Klebsiella pneumonia. Molecular operating environment performed virtual screening using molecular docking studies of the synthesized compounds. The results indicated that some prepared compounds are suitable inhibitor against dihydrofolate reductase (DHFR) enzyme (PDBSD:4DFR) with further modification.     

Synthesis,characterization, antimicrobial activity and structure–activity relationships of new aryldisulfonamides

A series of aromatic disulfonamide (1-8) derivatives and 4-methylbenzenesulfonyl hydrazide (9) were synthesized and characterized. All compounds were evaluated in vitro for their antimicrobial activity against Staphylococcus aureus ATCC 25953, Bacillus cereus ATCC 6633, Bacillus magaterium RSKK 5117, Escherichia coli ATCC 11230, Salmonella enterititis ATCC 13076 by microdilution and disc diffusion methods. Antimicrobial activity of the aromatic disulfonamides decreased as the length of the carbon chain increased. An analysis of the structure- activity relationship (SAR) along with computational studies showed that the most active compound (9) possessed low lipophilicity (AlogP=0.59) and high solubility (logS = -1.33).