Synthesis,characterization, and antimicrobial activity of some new coumarin derivatives

A number of new [(4-methyl-2-oxo-2H-chromen-7-yl)amino]methylcoumarins (5a–c), benzofuran (6), and benzoxazol (7) were synthesized through the reaction of 7-amino-4-methylcoumarin (1) with a number of organic halides. In addition, series of N-substituted 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (11a–h) and (12a–d) were prepared from the reaction of 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (8) with corresponding heteroaryl/alkyl halides (2–4, 9, and 10). The synthesized compounds were characterized by elemental analysis and by spectroscopic techniques such as ¹H-NMR, ¹³C-NMR, and mass spectrometry and were tested for their in vitro antimicrobial activity. The newly synthesized compounds exerted significant inhibitory activity against the growth of tested bacterial strains and a few of them are found to be potent antimicrobial agents.     

Design and synthesis of novel piperazine unit condensed 2,6-diarylpiperidin-4-one derivatives as antituberculosis and antimicrobial agents

Abstract  

A new series of 1-[2-(4-ethoxycarbonylpiperazine-1-yl)acetyl]-2,6-diarylpiperidin-4-ones (3a–3j) has been synthesized by conventional method and were characterized by IR, elemental analysis, mass spectral, ¹H NMR, ¹³C NMR, and single crystal X-ray diffraction analysis. The synthesized compounds were evaluated for their antituberculosis activity against Mycobacterium tuberculosis H37Rv (ATCC-27294) and also its antimicrobial activity were examined against five familiar bacterial and fungal strains. Among the synthesized compounds, compounds 3e–3j exhibit higher inhibition potency (16 μg/ml) against M. tuberculosis H37Rv. Furthermore, compounds containing fluoro substituent in the phenyl ring at C-2 and C-6 positions of the piperidin-4-one motif (compounds 3c, 3d, and 3i) exerted better antibacterial and antifungal activity than the other phenyl-substituted compounds.     

EGFR tyrosine kinase targeted compounds: synthesis, docking study, and in vitro antitumor activity of some new quinazoline and benzo[d]isothiazole derivatives

The preparation of new quinazoline and benzo[d]isothiazole-based antitumor agents is described. The target compounds fall into three groups including the N-substituted derivatives 2a–d, the substituted amino derivatives 4–6a–d, and the dimeric compounds 7–9a,b. Docking study of the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. All compounds were tested, in vitro, for their activity against human mammary carcinoma cell line (MCF7) in which EGFR is highly expressed. All compounds showed significant growth inhibitory activity. The remarkable activity of the bis quinazoline derivative 8a (IC₅₀ = 0.06 μg/ml; 1.64 nmol/ml) is to be noted.     

Synthesis,antiproliferative activity,acute toxicity and assessment of the antiandrogenic activities of new androstane derivatives

A number of 17-oxo-5-androsten-3β-yl esters (9a–9f) and 3β-alkoxy-5-androsten-17-ones (11a–11e) were synthesized from commercially available (25R)-5-spirosten-3β-ol (Diosgenin) (4) as starting material. The synthesized compounds were evaluated for their antiproliferative activity against the prostate-specific cancer cell line DU-145, acute toxicity and effect on serum androgen levels, and compared with finasteride as positive control. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data and biological activity of the synthesized compounds are reported.     

Design, synthesis, antifungal activity, and ADME prediction of functional analogues of terbinafine

From the earlier quantitative structure–activity relationship (QSAR) and molecular modeling studies, a series of quinoline derivatives 5a–h mimicking terbinafine and containing different bulky aromatic rings in the side chain were designed using LeapFrog, a de novo drug design program. The designed compounds were synthesized and screened for antifungal activity in vitro against C. albicans. Of the ten compounds designed and synthesized, compounds 5c, d, f, h, and i exhibited minimum inhibitory concentration (MIC) in the range 4–25 μg/ml and were further evaluated for oral toxicity in animal model. The pharmacokinetic properties for these compounds were estimated in silico and compared with terbinafine. Compound 5h, N-methyl-N-[(2-naphthyl)methyl]-8-quinolinemethanamine, was found to be least toxic, possessing pharmacokinetic parameters close to those of terbinafine.     

Novel antitubercular diallyl/dibenzylthiosemicarbazones endowed with high activity toward multi-drug-resistant tuberculosis

Novel diallyl and dibenzylthiosemicarbazones were prepared by three-step reactions. The compounds were tested for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug-resistant Mycobacterium tuberculosis (MDR-TB). Most of the compounds showed excellent activity toward MDR-TB. Among the thirty compounds (4,5a–o) tested N,N-dibenzyl-2-((5-nitrofuran-2-yl)methylene)hydrazinecarbothioamide (5g) was found to be the most potent compound MICs of 0.55 and 0.12 μM against MTB and MDR-TB.     

Iodine (III)-mediated synthesis of some 2-aryl/hetarylbenzoxazoles as antibacterial/antifungal agents

Ten 2-aryl/hetarylbenzoxazoles (5a, 5b, and 6a–h) were synthesized via oxidative cyclization of Schiff bases (3a, 3b, and 4a–h) with 1.1 equivalent of iodobenzene diacetate (IBD) in methanol. All of these 2-aryl/hetarylbenzoxazoles (5a, 5b, and 6a–h) were tested in vitro for their antibacterial and antifungal activities against Bacillus subtilis, Bacillus stearothermophilus, Escherichia coli, and Pseudomonas putida. These compounds also were screened for their antifungal activity against Aspergillus flavus and Aspergillus niger. Biological activity of these compounds was compared with those of commercially available antibiotics, chloramphenicol and antifungal agent cycloheximide. Most of these compounds, 5a, 5b, 6a, 6b, 6d, 6e, 6g, 6h, were equipotent or more potent than these commercial drugs at concentration 100 μg/ml.     

Conventional and microwave-assisted synthesis of imidazole and guanidine derivatives and their biological evaluation

A number of imidazole derivatives 3a–f and 4a–f have been synthesized by the condensation of 3-methylthiophen-2-carboxaldehyde 1a, 5-methylthiophen-2-carboxaldehyde 1b, N-methylpyrrol-2-carboxaldehyde 1c, 1-naphthaldehyde 1d, 2-naphthaldehyde 1e, and 2-hydroxy-1-naphthaldehyde 1f with 1,2-diaminoanthraquinone 2a and 2,3-diaminophenazine 2b, respectively. Condensation of 2-guanidinobenzimidazole with functionalized aldehydes 1a–f leads to the formation of guanidine derivatives 5a–f. Both imidazole (3a–f, 4a–f) and guanidine derivatives (5a–f) were synthesized in good yields using conventional heating and microwave irradiation techniques. Structures assigned to compounds 3a–f, 4a–f and 5a–f are supported by correct spectral and analytic data. On screening for anti-inflammatory and anticancer activities, compounds 3e, 4a and 5a exhibited good anti-inflammatory and compounds 3d, 3f, 4d and 4f showed very good anticancer activity.     

Synthesis and antimicrobial activities of some new 5-((3-(aryl)-1-phenyl-1H-pyrazol-4-yl)methylene)-3-phenylthiazolidine-2,4-diones

A series of nine new compounds of 5-((3-(aryl)-1-phenyl-1H-pyrazol-4-yl)methylene)-3-phenylthiazolidine-2,4-diones was synthesized by Knoevenagel condensation of various 3-(aryl)-1-phenyl-1H-pyrazole-4-carbaldehydes with 3-phenylthiazolidine-2,4-dione in ethanol in the presence of piperidine as a catalyst. The reaction afforded the desired products in good yields. All the nine compounds were screened for their in vitro antibacterial (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli) and antifungal (Aspergillus niger and A. flavus) activity. Biological activities of these compounds were compared with those of commercially available antibiotics, ciprofloxacin and antifungal agent fluconazole. Two compounds 3e and 3i were found to be most effective against S. aureus and B. subtilis. Out of the nine compounds tested for antifungal activity, five, 3c–f and 3h showed more than 50% inhibition against the A. flavus, whereas the three compounds 3a, 3d and 3f showed more than 50% inhibition against A. niger.     

Synthesis, in vitro cytotoxicity, and antibacterial studies of new asymmetric bis-1,2,4-triazoles

A series of asymmetric bis-1,2,4-triazoles (4a–l) were synthesized from respective 1,2,4-triazole-3-thiocarbohydrazides (2a, b) via base catalyzed dehydrative cyclization of thiosemicarbazide intermediates (3a–l). The synthesized compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, and Mass spectral studies. The asymmetric bis-1,2,4-triazole derivatives (4a–l) were evaluated for in vitro antioxidant activity by DPPH radical scavenging assay method. The compounds with significant antioxidant potential were evaluated for in vitro cytotoxicity by MTT assay method against HT29 (Human adenocarcinoma) and MDA-231 (Human breast cancer) cancer cell lines. All the synthesized compounds were evaluated for in vitro antibacterial activity against Bacillus subtilus (ATCC 6633), Staphylococcus aureus (ATCC-25923), Escherichia coli (ATCC-25922), and Pseudomonas aeruginosa (ATCC-27853).     

Potential anti-inflammatory activity and ulcerogenicity study of some novel pyrimido[4′,5′:4,5]pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>]azepine derivatives

A series of novel tricyclic pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepine derivatives were synthesized using the starting compound 3-amino-1-oxo-2-phenyl-5-(pyrrolidin-1-yl)-1,2,4a,5,6,7,8,9-octahydropyrimido[1,6-a]azepine-4-carbonitrile 4. This series includes the 3-aryl derivatives 6a, b, the 3-cycloaminoalkyl derivatives 8a–f, the 3-mercaptomethyl derivatives 10 and 11a, b, the 2-cycloaminomethyl derivatives 13a–c, the 1-cycloamino derivatives 15a–c and the 1-amino derivative 16. The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw oedema test in rats using diclofenac sodium as the reference drug. Ulcer indices for the most active compounds were calculated. The 3-mercaptomethylacetic acid derivative 10 was the most active compound, showing activity comparable to diclofenac sodium with minimal ulcerogenic effect while the rest of the tested compound exhibited moderate anti-inflammatory activity.     

Synthesis and antibacterial evaluation of series of novel tri-substituted-s-triazine derivatives

Two novel series of s-triazine derivatives (6a–e and 7a–f) were synthesized with various aromatic and heterocyclic amines. The synthesized compounds were subsequently evaluated for their in vitro antibacterial activity against three gram-positive viz. Bacillus subtilis (NCIM-2063), Bacillus cereus (NCIM-2156), Staphylococcus aureus (NCIM-2079) and gram-negative bacteria viz. Pseudomonas aeruginosa (NCIM-2036), Escherichia coli (NCIM-2065) and Klebseilla pneumoniae (NCIM-2706) by the broth dilution method as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) using streptomycin as reference standard. Structures of the synthesized compounds were elucidated on the basis of elemental analyses and spectral data.     

Synthesis of pyrimidine and condensed pyrimidine derivatives and their evaluation for anti-inflammatory activity

Condensation of various amines (Ia–c) with 4-isothiocyanato-4-methyl-2-pentanone (2a) at room temperature gave tetrahydropyrimidinethiones (3a–c) whereas condensation of 1a–e with 3-isothiocyanatobutanal at room temperature gave tetrahydropyrimidinethiones (4a–e). Amines 1a, d, f–i on condensation with 4-isothiocyanato-4-methyl-2-pentanone (2a) by heating under reflux for 8 h at pH ~4 (for 1a, d) and at RT (for 1f–i) gave dihydropyrimidinethiones 5a–b and 5c–f, respectively. Condensation of 1f with 3-isothiocyanatobutanal gave dihydropyimidinethione 6. When isothiocyanate (2a) and phenylenediamine derivatives 1g, h were heated under reflux at pH ~4, tricyclic compounds 7a, b were obtained in good yields. Condensation of 3-isothiocyanatobutanal with o-phenylenediamines 1h and 1j at pH ~ 5 by refluxing in methanol for 8 h gave products 8 and 9. All these compounds were screened for anti-inflammatory activity. Compounds 3c, 4c and 7a exhibited anti-inflammatory activity comparable to standard drug ibuprofen.     

Synthesis and biological activity studies of new hybrid molecules containing tryptamine moiety

The synthesis of N′-(4-substitutedphenylsulfonyl)-2-{4-[2-(1H-indol-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazides (3a–c), 2-{4-[2-(1H-indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N′-aryl methylidene acetohydrazides (4a–f) and 4-[2-(1H-indol-3-yl)ethyl]-5-(4-substitutedbenzyl)-2-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a, b) was performed starting from the corresponding acid hydrazides (2a, b) which was reported earlier. The treatment of 1,3,4-oxadiazole derivatives (5a, b) with hydrazine hydrate produced 4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl derivatives (6a, b). Then, compound 6b was converted to the corresponding Schiff base (7) by the treatment with anisaldehyde. The synthesis of 5-(4-chlorobenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (8) and 5-(4-methylbenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (10) was carried out by the reaction of acid hydrazides (2a, b) with aryl iso(thio)cyanates either via the formation of the intermediates (9a, b) (for 10) or direct cyclization (for 8). 1,3-Oxa(thia)zol-2(3H)-ylidene]acetohydrazide derivatives (11a, b) were obtained by the reaction of 9a, b with 4-chlorophenacyl bromide. All newly synthesized compounds were screened for their antimicrobial activities and some of which was found to be active against the test microorganisms.     

Synthesis and cytotoxicity of 1-phenylethanolamine carboxamide derivatives: effects on the cell cycle

Seven novel analogues of 1-phenylethanolamine carboxamide derivatives, 3a–3g, related to carboxamides isolated from Isodon excisus were synthesized and evaluated for their cytotoxic and apoptosis-induction properties against murine B16 and leukemia L1210 cell lines. Compounds containing no substitution at the 4′-position (3a–3d) or containing a 4′-amino (3e–3g) group were investigated. Generally, the amino-containing compounds were slightly more active than their unsubstituted congeners. Also, the indole-containing compounds 3c and 3f gave the strongest cytotoxic activity (IC₅₀ = 25–87 μM) against the growth of L1210 and B16 cancer cells. Compound 3f was subjected to flow cytometry studies and it was found to induce L1210 cells grown in culture to undergo apoptosis.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Synthesis of some substituted furan-2(5H)-ones and derived quinoxalinones as potential anti-microbial and anti-cancer agents

In search for novel anti-cancer and anti-microbial agents with promising pharmacotoxicological profile, the synthesis of some substituted 4-halofuran-2(5H)-ones (8a–l, 9, 11) and derived halogenated quinoxalin-2(1H)-ones (12a–d) is described. Some of the halogenated furanones were readily oxidized to the corresponding 2-bromo-2-propenoic acids (13a–c) with hydrogen peroxide in alkaline medium. Twenty-two compounds were preliminary tested for their in vitro activity against three bacteria and one fungus and revealed encouraging activity. On the other hand, three compounds were screened as anti-cancer agents using cell line panel protocol and 22 compounds were subjected to cycline-dependent kinases (CDKs) inhibition screening program but were inactive.     

17-Oximino-5-androsten-3��-yl esters: synthesis, antiproliferative activity, acute toxicity, and effect on serum androgen level

Abstract  

The 17-oximino-5-androsten-3β-yl esters (10a–10j) were synthesized from commercially available (25R)-5-Spirosten-3β-ol (Diosgenin) (4) as starting material. The synthesized compounds were evaluated for their antiproliferative activity against prostate specific cancer cell line DU-145, acute toxicity, and effect on serum androgen level and were compared with Finasteride used as positive control. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data, and biological evaluation for the synthesized compounds are reported.     

Quinolinedione nucleus as a novel scaffold for A1 and A2A adenosine receptor antagonists

In the last few years, much effort has been directed towards the synthesis of selective adenosine receptor (AR) antagonists since they are attractive tools for pharmacological intervention in many pathophysiological conditions. During our studies aimed at obtaining new nonclassical adenosine antagonists devoid of phosphodiesterase (PDE) inhibition, a series of 2-pyridones and 2,5-quinolinediones (3a–f, 5a–f, 6a,c–f) has been synthesized as potential AR ligands. Binding affinities of the new compounds were determined for bovine and human adenosine A₁, A_2A, and A₃ receptors. Compound 5f showed good affinity (K _i = 7.8 μM) towards human A₁AR but no selectivity (K _i = 7.0 μM) towards human A_2AAR, whereas compound 6f showed more affinity towards human A_2A (K _i = 16 μM) than A₁ receptor (percentage inhibition at 10 μM concentration = 11). In the 1–100 μM range, the new compounds did not inhibit cardiac PDE3 activity at all. Molecular modeling studies carried out on 5f and 6f support the pharmacological results and suggest 6f as a potential lead compound selective towards A_2AAR.     

Synthesis of benzo[b][1,4]oxazin-3(4H)-ones via smiles rearrangement for antimicrobial activity

The benzo[b][1,4]oxazin-3(4H)-one derivatives, 1a–p, carrying F, Br, and Cl on the benzene ring, or benzyl, cyclohexyl, n-hexyl, and tetrafuryl methylene groups attached to nitrogen atom were synthesized via Smiles rearrangement and assayed in vitro for their antimicrobial activity against Gram-positive, Gram-negative bacteria, and fungi. The antimicrobial activity of the benzo[b][1,4]oxazin-3(4H)-ones showed, on the whole, potency toward all the tested Gram-positive and Gram-negative microorganism (MIC ranging from 16 to 64 μg/ml), whereas weak effectiveness was exhibited against fungi. Data obtained suggest that fluorine atom in the compounds, 1c, 1f, 1i plays an important role in enhancing the antimicrobial properties of this class of compounds. These observations provide some predictions to design further antimicrobial active compounds prior to their synthesis according to molecular modeling studies.