In vitro evaluation of the antibacterial and antifungal activity of some new pyrazolyl-quinazolin-4(3<Emphasis Type="Italic">H</Emphasis>)-one derivatives

Several pyrazolyl-quinazolin-4(3H)-ones 6a–m were synthesized by the cyclization of acrylamides 5a–m with hydrazine hydrate. The overall reaction was carried out by multi step process. The base-catalyzed cyclization of acid chloride 1 with 5-iodo anthranilic acid yielded benzoxazinone 2, which on reaction with hydrazine hydrate afforded amino quinazolin-4(3H)-one 3. The acrylamides 5a–m were easily synthesized by acetylation and then condensation with aromatic aldehyde of quinazolin-4(3H)-one 3. The structural confirmation of the synthesized compounds was carried out on the basis of elemental analyses as well as IR and NMR spectral results. The title compound 6a–m was evaluated for antibacterial and antifungal activity in vitro.     

Synthesis and antibacterial activity of some new 1-aroyl-3-(substituted-2-benzothiazolyl)thioureas

An efficient, synthesis of some new 1-aroyl-3-(substituted-2-benzothiazolyl)-thioureas is reported. Substituted anilines were treated with potassium thiocyanate and bromine in acidic medium to afford the corresponding 2-amino-benzothiazoles (2a–e). Treatment of the latter with suitably substituted aroyl isocyanates, produced in situ by reaction of corresponding aroyl chlorides with thiocyanate in acetone, afforded the 1-aroyl-3-(substituted-2-benzothiazolyl)thioureas (3a–k). The structures were confirmed by physical, IR, NMR, and mass spectral data. The synthesized compounds (2a–d, 3a–k) were assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and were found to exhibit moderate to potent activity towards the tested microorganisms, as compared to the standard drugs.     

Synthesis and antimicrobial study of fluoroquinolone-based 4-thiazolidinones

The title compounds 2-substituted phenyl-3-{1-cyclopropyl-6-fluoro-7-[4-(4-methoxyphenylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline} carboxamido-1,3-thiazolidin-4-ones 6a–j have been synthesized from lead molecule 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1; this reacted with thionyl chloride to give acid chloride 2 and with hydrazine hydrate to afford hydrazide 3. The hydrazide 3 on condensation with substituted aromatic aldehydes a–j gave Schiff base; these on reaction with N-(4-methoxyphenyl) piperazine and thioglycolic acid furnished title compounds 6a–j. All of the synthesized compounds have been established by elemental analysis. IR and NMR spectral data and have been screened for antifungal and antibacterial activities.     

Simple and efficient synthetic routes to bioactive s-triazinyl dithiocarbamate derivatives

Series of 2,4-diarylamino-6-[N-(3′-methylphenyl)dithiocarbamoyl]-s-triazines (4a–l) and 2,4-bis[N-(3′-methylphenyl)dithiocarbamoyl]-6-arylamino-s-triazines (7a–l) were synthesized by two different synthetic routes. In the first route (A), 2,4,6-tricholoro-s-triazine (1) was condensed with N-(3-methylphenyl)ammoniumdithiocarbamate to afford compounds 3 or 6, which on reaction with different aryl amines afforded compounds 4a–l or 7a–l. In the second route (B), condensation of 1 with different aryl amines yielded compounds 2a–l or 5a–l. On further treatment with N-(3-methylphenyl)ammoniumdithiocarbamate these afforded compounds 4a–l or 7a–l. The newly synthesized compounds 4a–l and 7a–l were characterized by elemental analyses, infrared (IR), and ¹H nuclear magnetic resonance (NMR) spectroscopic investigation. All the products were evaluated for their antibacterial and antifungal activity.     

Synthesis,anti-inflammatory,analgesic, and antibacterial activities of some triazole,triazolothiadiazole, and triazolothiadiazine derivatives

This study is concerned with the synthesis of new 1,2,4-triazoles, 1,3,4-thiadiazoles, and 1,3,4-thiadiazines derivatives. Derivatives 3a–i were obtained by condensation of 4-amino-3-(4-pyridine)-5-mercapto-1,2,4-triazole 1 with the appropriate aldehyde. Compounds 4a–i were synthesized in a one pot reaction involving compounds 3a–i, formaldehyde, and morpholine. Condensation of compound 1 with the appropriate acids or 4-substituted phenacyl bromide gave compounds 6a–d and 8a–f respectively. The chemical structures of the newly synthesized derivatives were elucidated using different spectral and elemental methods of analysis. All compounds were evaluated for their anti-inflammatory activity and the most potent derivatives were tested for their analgesic activity using indomethacin as a reference drug. In addition, ulcerogenicity and LD₅₀ for the most active compounds were evaluated. Moreover, the antibacterial activities of the newly synthesized derivatives were investigated.     

Synthesis and antimicrobial activity of new pyridine derivatives-I

2-Amino substituted benzothiazoles 2a–l and 2-chloropyridine-3-carboxylic acid 3 were used to prepare 2-[N-(substitutedbenzothiazolyl)amino]pyridine-3-carboxylic acids (4a–l) in 2-ethoxy ethanol. Acid chlorides (5a–l) were condensed with 2-hydroxyethyl piperazine (6) and 2,3-dichloropiperazine (7) to prepare amide derivatives 2-[N-(substituted benzothiazolyl)amino]pyridin-3-yl(4-(2-hydroxyethyl)piperazin-1-yl)methanones (8a–l) and 2-[N-(substituted benzothiazolyl) amino]pyridin-3-yl(2,3-dichloropiperazine-1-yl)methanones (9a–l), respectively. The structures of new compounds have been established on the basis of elemental analysis and spectral (IR, ¹H NMR, and Mass spectra) studies. The in vitro antimicrobial activity was screened for all the synthesized compounds. Variable and modest activity were observed against the investigated strains of bacteria and fungi.     

Synthesis of new pyrazole,triazole, and thiazolidine-pyrimido [4, 5-b] quinoline derivatives with potential antitumor activity

2-Hydrazinyltetrahydropyrimido [4, 5-b] quinolin-4(3H)-one (3) was prepared by desulfurization reaction of S- and N-dimethyl derivatives 2 with hydrazine hydrate. Reactions of (3) with malonitrile, carbondisulfide, potassium thiocyanate, phthalic anhydride and aromatic aldehydes afforded 3, 5-di aminopyrazolopyrimido [4, 5-b] quinoline (4), triazolotetrahydropyrimido [4, 5-b] quinoline (5), aminotriazolopyrimido [4, 5-b] quinoline (6), aminophthalimidopyrimido [4, 5-b] quinoline (7) and N-arylidene hydrazinepyrimido [4, 5-b] quinoline 8a–d, respectively. Furthermore, 8a–d reacted with mercaptoacetic acid gave the thiazolidinonepyrimido [4, 5-b] quinoline 9a–d, which afforded the thiazolotriazolopyrimido [4, 5-b] quinolinone 10a–d upon treatment with ethanolic potassium hydroxide. The newly synthesized compounds were characterized by elemental analyses, IR, 1H-NMR, 13C-NMR and mass spectrometer. The investigated compounds were screened for their cytotoxicity. Compounds 4, 6 and 5 exhibited potent antitumor activity.     

cAMP-dependent phosphodiesterase inhibition and SAR studies on novel 6,8-disubstituted 2-phenyl-3-(substituted benzothiazole-2-yl)-4[3H]-quinazolinone

Two series of 6,8-disubstituted-2-phenyl-3-(substituted benzothiazole-2-yl)-4[3H]-quinazolinone (1–13 and 14–26) were synthesized by reported method and evaluated for their phosphodiesterase inhibitory activity. All test compounds exhibited good activity. The structure–activity relationships based on the results obtained for these series were also studied. In both series, electron-withdrawing substitutions showed more activity. Among the tested compounds 6,8-dibromo-2-phenyl-3-(5-chloro benzothiazole-2-yl)-4[3H]-quinazolinone (20) and 6,8-dibromo-2-phenyl-3-(6-nitro benzothiazole-2-yl)-4[3H]-quinazolinone (24) were found to be even more potent than theophylline (IC₅₀ of 1438 ± 85 μM for 20 and 1520 ± 48 μM for 24). Presented at National Symposium on Challenges in Drug Discovery Research: Networking opportunities between Academia & Industries April 7th–8th, 2006 at Birla Institute of Technology & Science, Pilani and submitted to Nagpur University as an M-pharm thesis.     

Triazenoindazoles and triazenopyrazolopyridines: Design,synthesis, and cytotoxic activity

Several triazenoindazoles 3a–e and triazinopyrazolopyridines 6a–i were prepared through the reaction of the corresponding 3-amino-4-chloroindazole and 3-aminopyrazolopyridine diazonium salts 2 and 5 with a number of secondary amines. All compounds were evaluated for their in vitro cytotoxic activity on three cell lines, HepG2, MCF7, and HeLa. Most compounds inhibited cell growth with IC₅₀ less than 0.1 μM. Compound 6d was the most potent, with an IC₅₀ of 0.03 μM against HepG2 and 0.05 μM against MCF7 and HeLa cells.     

Synthesis and antimicrobial activity of chalcone derivatives of indole nucleus

A series of previously unreported (2Z)-2-(1H-indol-1-yl)-3-(4-substituted phenyl)-1-phenylprop-2-en-1-one (5a–d) have been synthesized from easily accessible 2-(1H-indol-1-yl)-1-phenylethanone (3), which was obtained via a reaction of indole (1) with chloromethylphenyl ketone (2). The structures of the synthesized products have been elucidated using IR, ¹H NMR, and mass-spectroscopic data and elemental analyses. The final products were screened for their antimicrobial activity. Excellent results were obtained against both bacteria and fungi. In conclusion, we have developed a novel, convenient and simple method for the preparation of indole – chalcone hybrid compounds via the reaction of indole derivative with carbonyl compounds in the presence of a strong base. The rapid conversion, excellent yield, utilization of a base, and operational simplicity are great advantages of the proposed method.     

Synthesis and antimicrobial activity studies of some novel substituted phenylhydrazono-1H-tetrazol-5-yl-acetonitriles

Abstract  

In this study, some substituted phenylhydrazono-1H-tetrazol-5-yl-acetonitriles have been synthesized (2a–o, 2a and 2k are known compounds). The synthesized compounds were characterized by spectroscopic methods [Fourier-transform infrared (FTIR), nuclear magnetic resonance (NMR), mass spectroscopy (MS)]. In addition, antimicrobial activities of synthesized compounds were investigated against Bacillus cereus RSKK 863, Escherichia coli ATCC 3521, Pseudomonas aeruginosa ATCC 2921, and Staphylococcus aureus TP32. These compounds had antimicrobial effect against these bacteria (except for 2l).     

Synthesis,antioxidant and antimicrobial evaluation of simple aromatic esters of ferulic acid

Aromatic ester derivatives of ferulic acid where the phenolic hydroxyl is free (6a–d) or acetylated (5a–d) were evaluated for their antioxidant and antimicrobial properties. The superoxide radical scavenging capacity of compounds 5d and 6d–e (IC₅₀ of 0.19, 0.27 and 0.20 mM, respectively) was found to be twice as active as α-tocopherol (IC₅₀ = 0.51 mM). DPPH radical scavenging capacity was moderate and only found in compounds bearing free phenolic hydroxyl groups (6a–e). With regard to antimicrobial properties, compounds 6b and 6c displayed significant activity against Enterococcus faecalis (MICs = 16 μg/mL) and vancomycin-resistant E. faecalis (MIC for 6b, 32 and for 6c, 16 μg/mL). Compound 6c also demonstrated prominent activity against planktonic Staphylococcus aureus with a MIC value of <8 μg/mL and it inhibited bacterial biofilm formation by S. aureus with a MBEC value of <8 μg/mL, which was 64 and 128 times more potent than ofloxacin and vancomycin, respectively.     

Synthesis and anti-congestive heart failure activity of novel levosimendan analogues

A series of levosimendan analogues were designed and synthesized, employing the Friedel–Crafts reaction, hydrolysis, and cyclization from the key intermediate compound R(−)-6-(4-aminophenyl)-5-methyl-4, 5-dihydro-3(2H)-pyridazinone, which was obtained from the starting material, acetanilide. These compounds, except 1b, exhibited potent anti-congestive heart failure activities, especially the compounds 1e and 1k, which showed more effective action than levosimendan.     

Synthesis of certain mercapto-and aminopyrimidine derivatives as potential antimicrobial agents

Reaction of ethyl 4-chloro-2-phenylpyrimidine-4-carboxylate (4) with 5-chloro-2-methylthiophenol or 3-aryl-4-phenyl-1,2,4-triazole-5-thiol yielded the corresponding thioethers (5) and (8a, b), respectively. Careful alkaline hydrolysis of (5) yielded the corresponding carboxylic acid (6). Reaction of (4) withp-aminoacetophenone yielded compound (10) which was reacted with certain aromatic aldehydes to afford the α, β-unsaturated ketones (11a–d). Condensation of (11a–d) with malononitrile or phenylhydrazine yielded the 2-amino-3-cyanopyridines (12a–f) or the 2-pyrazolines (13a, b), respectively. Seven representative compounds were tested for theirin vitro antimicrobial activity against some pathogenic micro-organisms, some of them were proved to be active.     

Synthesis of novel isatin-thiazoline and isatin-benzimidazole conjugates as anti-breast cancer agents

A series of new isatin-thiazoline 3a–h and isatin-benzimidazole 4a–h derivatives were synthesized via condensation of isatin Mannich bases 2a–h with either 2-aminothiazoline or 2-aminobenzimidazole. The structures of the newly synthesized compounds were characterized by spectral data. The anti-breast cancer activity of some of the synthesized compounds was assessed in the MCF-7 human breast cancer cell line. The results showed that compounds 4b, 4d and 4g possess significant antiproliferative activity against MCF-7 cells.     

Synthesis and cytostatic evaluation of some 2-(5-substituted-2-oxoindolin-3-ylidene)-N-substituted hydrazine carbothioamide

Various substituted 2-(5-substituted-2-oxoindolin-3-ylidene)-N-substituted hydrazine carbothioamide 4a–g and 2-(5-substituted-1-(4-substituted benzyl)-2-oxoindolin-3-ylidene)-N-substituted hydrazine carbothioamide 5a–k were synthesized. The compounds were evaluated for their cytostatic activity against human Molt4/C8 and CEM T-lymphocytes as well as murine L1210 leukemia cells. Several of these compounds were endowed with low micromolar 50%-inhibitory concentration (IC₅₀) values, and some were virtually equally potent as melphalan. The most potent inhibitors against the murine leukemia cells were also most inhibitory against human T-lymphocyte tumor cells. 2-(5-fluoro-1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-N-p-tolylhydrazine carbothioamide (5b) emerged as the most potent cytostatic compound among the tested compounds. The encouraging cytostatic data provide an adequate rationale for further modification of these molecular scaffolds.     

Synthesis of new 1,2,4-triazoles as anti-inflammatory and anti-nociceptive agents

A series of fifteen new substituted 1,2,4-triazoles (6a – 6o) have been synthesized in order to obtain new agents with potential anti-inflammatory and anti-nociceptive activity. The title compounds were synthesized using 4-methylbenzoic acid as a starting reactant. The synthesized compounds were characterized by spectroscopic methods (IR, ¹H NMR, ¹³ C NMR, FAB⁺ − MS) and elemental analysis (nitrogen analysis). The title compounds were evaluated for anti-inflammatory activity by the carrageenan induced paw edema method, and some compounds were evaluated for anti-nociceptive activity by the hot plate method and tail immersion method. Compounds N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-piperidin-1-ylacetamide (6f), 2-(4-benzylpiperazin-1-yl)-N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]acetamide (6i) and N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-morpholin-4-ylacetamide (6 k) showed significant anti-inflammatory activity compared to other synthesized compounds, and N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-morpholin-4-ylacetamide (6 k) exhibited superior anti-nociceptive activity.     

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.     

Synthesis of 6-aziridlnylbenzimidazole derivatives and theirin vitro antitumor activities

In search for new antitumor agents, twelve 6-aziridinylbenzimidazole derivatives were synthesized and their cytotoxicities were tested against three cancer cell lines (mouse lymphocytic leukemia P388 and B16, and human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a–d) were obtained by Phillips reaction. These benzimidazoles were then reacted with Fremy's salt to give a mixture of three 2-(acetoxymethyl) (8a–c) and four 2-(hydroxymethyl)benzimidazole-4,7-diones (9a–d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a–c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4,7-diones (11a–d). Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters10d and13e–h were prepared by the sequential reactions of esterification and addition. The synthesized compounds show potent cytotoxicity against all of three cell lines tested. The cytotoxicities of10a–d or11a–d against SNU-16 were superior to those of13e–h, and were equal to or slightly higher than that of mitomycin C. Compounds11a–d were slightly more cytotoxic than10a–d in all cell lines tested.     

Synthesis and evaluation of 2,6-piperidinedione derivatives as potentially novel compounds with analgesic and other CNS activities

New 2,6-piperidinediones 2_a–g and 4_a–d were prepared by initial condensation of aromatic aldehydes or cycloalkanones with cyanoacetamide to give α-cyanocinnamides l_a–g or cycloalkylidenes 3_a,b which underwent Michae1 addition with ethyl cyanoacetate or diethylmalonate. Compounds 4_a–d were alkylated by various alkyl halides to produce the N-alkylated 2,6-piperidinedione derivatives 5_a–m. Some new selected compounds 2_a–c,f, 4_a–d & 5_e,h,j were pharmacologically evaluated for potential anticonvulsant, sedative and analgesic activities. These compounds exhibited significant anticonvulsant and analgesic effects after a single I.P. administration 100 mg/kg b.wt. . On the other hand all the investigated compounds induced hypnotic activity and prolonged the phenobarbital sodium- induced sleep as compared with the control group and the most potent compound was found to be 2_f.