Synthesis,antimicrobial, antiquorum-sensing and cytotoxic activities of new series of benzothiazole derivatives

New series of benzothiazole derivatives were designed and synthesized. The newly synthesized compounds were screened for their antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus cereus. Compounds 6j and 6o showed the highest activity against E. coli and S. aureus. The antifungal activity of these compounds was also tested against Candida albicans and Aspergillus fumigatus293. Compounds 4c, 4g and 6j exhibited the highest activity against C. albicans. In addition, compounds4 a and 6j displayed promising activity against A. fumigatus 293. The same compounds were examined for their antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, whereas compounds4 a, 6j and 6p showed moderate activity. The in vitro cytotoxicity testing of the synthesized compounds was performed against cervical cancer(Hela) and kidney fibroblast cancer(COS-7) cell lines. Results indicated that all tested compounds have IC50 values 50 mmol/L against both cell lines. Molecular properties, toxicities, drug-likeness, and drug score profiles of compounds 4a–c, 5a, 6g,h, 6j, 6l, 6o and7 c,d were also assessed.     

Synthesis,Anti‐Microbial,and Cytotoxic Activities Evaluation of Some New Pyrido[2,3‐d]Pyrimidines

Novel pyridine derivatives 1d and 7 , pyrido[2,3‐d]pyrimidine derivatives 2a , 2b , 2c , 2d , 3a , 3b , 3c , 3d , 4a , 4b , 4c , 4d , 5a , 5b , 5c , 5d , 6a , 6b , 6c , 6d , 8a , 8b , and 9a , 9b were synthesized and screened for their anti‐microbial and cytotoxic activities. Compounds 2b , 2c , 3b , 3c , 5b , 5c , 6b , 6c , and 7 showed excellent anti‐microbial activities against all the tested bacteria and fungi compared to the reference drugs. Furthermore, they exhibited high safety profile in cytotoxicity test except 2c and 3c . The structures of the newly synthesized compounds were confirmed by spectral data and elemental analysis.     

Synthesis and antimicrobial activity of some novel 5-alkyl-6-substituted uracils and related derivatives

6-chloro-5-ethyl-, n-propyl- and isopropyluracils 5a-c were efficiently prepared from the corresponding 5-alkybarbituric acids 3a-c via treatment with phosphorus oxychloride and N,N-dimethylaniline to yield the corresponding 5-alkyl-2,4,6-trichloro-pyrimidines 4a-c, which were selectively hydrolyzed by heating in 10% aqueous sodium hydroxide for 30 minutes. The reaction of compounds 5a-c with 1-substituted piperazines yielded the corresponding 5-alkyl-6-(4-substituted-1-piperazinyl)uracils 6a-j. The target 8-alkyltetrazolo[1,5-f]pyrimidine-5,7(3H,6H)-diones 7a-c were prepared via the reaction of 5a-c with sodium azide. Compounds 6a-j and 7a-c were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compound 6h displayed potent broad-spectrum antibacterial activity, while compound 6b showed moderate activity against the Gram-positive bacteria. All the tested compounds were practically inactive against Candida albicans.     

Synthesis and Some Chemical Behaviour of Certain Substituted Thiosemicarbazides

Three new thiosemicarbazides (1 a-c ) were prepared from N-[4-phenyl-5-(2-thienyl)-1,2,4-triazol-3-yl]mercaptoacetohydrazide. Reaction of (1 a-c) with the appropriate phenacyl bromide afforded thiazoline derivatives (2 a-i) whereas their reaction with chloroacetic acid or maleic anhydride gave the corresponding thiazolidine derivatives (3 a,b) and (4 a,b) . Cyclodesulfurization of (1 a-c) with DCCD in toluene yielded 5-substituted-amino-1,3,4-oxadiazoles (5 a,b) , while their dehydration with PPA gave the corresponding 5-substituted-amino-1,3,4-thiadiazoles (6 a-c) . Six representative compounds were tested for their in-vitro antimicrobial activity against some pathogenic microorganisms, some of them were proved to be active.     

Synthesis and antimicrobial activity of N'-heteroarylidene-1-adamantylcarbohydrazides and (±)-2-(1-adamantyl)-4-acetyl-5-[5-(4-substituted phenyl-3-isoxazolyl)]-1,3,4-oxadiazolines

The reaction of adamantane-1-carbohydrazide (1) with heterocyclic aldehydes, namely 5-(4-chlorophenyl)isoxazole-3-carboxaldehyde (2a), 5-(4-methylphenyl)isoxazole-3-carboxaldehyde (2b), 5-(4-methoxyphenyl)isoxazole-3-carboxaldehyde (2c), 1H-imidazole-2-carboxaldehyde and 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde, in ethanol, yielded the corresponding N'-heteroarylidene-1-adamantylcarbohydrazides 3a, 3b, 3c, 4 and 5, respectively, in good yields. The 4-acetyl-1,3,4-oxadiazoline analogues 6a?c were prepared in 48-55% yields by heating their corresponding N'-heteroarylidene-1-adamantylcarbohydrazides 3a-c with acetic anhydride for two hours. Compounds 3a-c, 4, 5 and 6a-c were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 4 and 5 displayed potent broad-spectrum antimicrobial activity, while compounds 3a-c showed good activity against the Gram-positive bacteria.     

Synthesis and antidiabetic activity of novel triazole derivatives containing amino acids

New series of triazole derivatives coupled with amino acids 1a-h were obtained via multicomponent reaction of 2-hydroxy benzaldehyde or 2-hydroxy acetophenone with thiosemicarbazide and different amino acids. The obtained compounds were reacted with p-toluinesulfonyl chloride 2 to give the corresponding sulfonamides 3a-h . Compound 1b was allowed to react with different aromatic aldehydes or cyclic ketone under alkaline conditions to afford the expected imino compounds 4a-d and 6a-c , respectively. These compounds were allowed to react with ethyl glycolate to yield the expected thiazolidinone derivatives 5a-d or 7a-c , respectively. Structures of the newly synthesized compounds were found to be in accordance with their elemental analyses and spectral data. The obtained compounds exhibited very prominent in vitro and in vivo antihyperglycemic effect at a dose of 40 mg/kg body weight compared to the standard drug gliclazide and control. The antidiabetic effect was investigated using oral glucose tolerance test in normal and non-insulin-dependent diabetes mellitus (NIDDM) in STZ-rat model. Compounds 3a - h , 5b , 5c , 5d , 7a , 7b , and 7c showed significant activity in lowering blood glucose (more than 80%) compared to the NIDDM control.     

Synthesis of some novel pyrazoline‐thiazole hybrids and their antimicrobial activities

A series of novel thiazolyl pyrazolines 7a‐h , 9a‐f , and 11a‐f have been synthesized by the reaction of thioamide derivatives 5a , b with 1‐aryl‐2‐bromoethanones 6a‐d , chloroacetones 8a‐c , and hydrazonoyl chlorides 10a‐c . Additionally, pyrazoles 15a‐c and 20 were prepared starting from enaminone 13 . These newly synthesized compounds were screened for their in vitro antibacterial activity against four bacterial species. Compound 11b showed a moderate activity against Klebsiella pneumoniae. Compounds 7c and 11c revealed a moderate activity against Pseudomonas aeruginosa. In addition, the antifungal activity of the newly synthesized compounds was determined against five fungal strains. Compounds 7e , 7g , and 11e showed a good activity against Aspergillus flavus and Penicillium expansum.     

Synthesis,Structural Characterization,and Biological Evaluation of Novel Substituted 1,3‐Thiazole Derivatives Containing Schiff Bases

In this study, thiazole derivatives containing Schiff bases ( 7a , 7b , 7c , 7d , 7e , 7f , 8a , 8b , 8c , 8d , 8e , 8f , 9a , 9b , 9c , 9d , 9e , 9f ) were synthesized in moderate to high yields (49–94%) using the Hantzsch reaction with thiosemicarbazone derivatives ( 5a , 5b , 5c ) and 2‐bromo‐1‐phenylethanone derivatives ( 6a , 6b , 6c , 6d , 6e , 6f ). The structures of synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, elemental analyses, mass spectroscopy and X‐ray diffraction analysis techniques. Moreover, the synthesized compounds were tested for their in vitro antifungal activity and most of them exhibited moderate to good activity against Fusariumoxysporumf.sp. lycopersici.      

Synthesis and anticonvulsant activity of some quinazolin-4-(3H)-one derivatives

A number of 3-substituted-2-(substituted-phenoxymethyl) quinazolin-4(3H)-one derivatives 4a,b, 5a-c, 6, 7a-f, 8a-e and 9a,b have been synthesized. Their structures have been elucidated on the basis of elemental analyses and spectroscopic studies (IR, 1H-NMR, MS). A preliminary evaluation of the anticonvulsant activity of the prepared compounds has indicated that compounds 4b, 7b-f, 8a and 9b exhibit significant anticonvulsant activity, while compounds 6, 8b and 8d show mild to moderate activity.     

Saturated heterocycles. Part 216 . Synthesis,structure and ring opening of trans-perhydro-1,4-benzoxazepin-3-one derivatives

trans-Perhydro-1,4-benzoxazepin-3-ones 2a-c were synthesized and transformed to condensed-skeleton perhydro-trans-1,4-benzoxazepines 3a,b , the thiones 4a,b , the urea derivatives 5a,b , and N-acylated compounds 6a-e . Compounds 6b,d were ring-opened by hydrochloric acid in ethanol to yield trans-2-(1-carbethoxyethoxy)-1-acylaminomethylcyclohexane derivatives 7b,d . The ¹H- and ¹³C-nmr investigation and X-ray analysis of 5b and 6c,d proved that the expected N-acylated derivatives were formed and that both rings of the trans anellated compounds have a chair conformation.     

Design,synthesis, characterization and antimicrobial evaluation of some novel hydrazinecarbothioamide, 4-thiazolidinone and 1,2,4-triazole-3-thione derivatives

A series of novel hydrazinecarbothioamide ( 5a,c,f ), 4-thiazolidinone ( 6a - e ), and 1,2,4-triazole-3-thione ( 7a - d ) were designed and synthesized. The structural elucidations of the novel compounds were performed by IR, ¹H-NMR, ¹³C-NMR, mass and elemental analysis. All novel derivatives were evaluated for their antibacterial and antifungal activities against nine diverse microorganisms. According to the biological activity studies of the compounds, 6d , 7c and 7d displayed hope promising antibacterial activity. Furthermore, 6d displayed potent antifungal activity. Consequently, the obtained results revealed that 6d , 7c and 7d present a leading structure for future drug development due to its straightforward synthesis and relevant bioactivity.     

Synthesis,photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones

The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.     

Synthesis and biological activities of some new thiazolidine derivatives containing pyrazole ring system

As a part of systematic investigation of synthesis and biologically active compounds of thiazolidine (TZD) derivatives containing pyrazole ring system, several new pyrazole–TZD derivatives 8a , 8b , 8c , 8d and 9a , 9b , 9c , 9d have been synthesized. Compounds 8a , 8b , 8c , 8d were prepared from N‐substituted TZDs 6a , 6b , 6c , 6d and 1H‐pyrazole‐4‐carboxaldehyde 7 by Knoevenagel‐type reaction. Treatment of 8a , 8b , 8c , 8d with sodium hydride at room temperature caused dimerization reaction to afford the corresponding spirocompounds 9a , 9b , 9c , 9d . All the synthesized compounds were characterized by spectroscopic analysis. In vitro, the synthesized compounds 8a , 8b , 8c , 8d and 9a , 9b , 9c , 9d were tested for their growth inhibitory activity in A549 lung cancer, B16F10 murine melanoma, and HeLa human uterine carcinoma cells and for their differentiation of 3T3‐L1 preadipocytes to adipocytes. The results showed that compound 8c possessed growth inhibitory effect of B16F10 cells (IC₅₀ = 27 μM) and compounds 9c , 9d had induction effect on the differentiation of 3T3‐L1 preadipocytes. J. Heterocyclic Chem., (2011).     

Synthesis,Characterization, and Screening for Anti‐inflammatory and Antimicrobial Activity of Novel Indolyl Chalcone Derivatives

Because of the great biological importance of substituted indole derivatives, in the present study, a series of pyrazolylindole, thiazolylindole, and pyrimidinylindole derivatives have been synthesized with good yield. The precursor indolyl chalcone 2a – d was prepared by reaction of 3‐chloro‐1H‐indole‐2‐carbaldehyde 1 with different ketones. Then, compounds 3b – d , 4 , and 5a – d have been synthesized by the reaction of chalcones 2a – d with hydrazine, phenylhydrazine, and thiosemicarbazide. When the chalcone derivative 2b subjected to react with hydroxylamine hydrochloride gave isoxazolylindole derivative 6b . N‐thiazolidine pyrazolyl indole 7 was obtained by reacting compound 5a with ethyl chloroacetate. On the other hand, when chalcone derivative 2b allowed to react with urea and thiourea gave the corresponding pyrimidinylindole derivatives 8 and 9 . Finally, when chalcone derivative 2b reacted with ethyl cyanoacetate or malononitrile gave pyridinylindole derivatives 10 and 11 . The structures of the all synthesized compounds were elucidated on the basis of spectral analysis infrared, NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their antimicrobial and anti‐inflammatory activity. Compound 4b was the highest antibacterial activity against all strains of bacteria with values higher than those of the corresponding reference antibiotics (ciprofloxacin and levofoxacin, respectively) and almost the same as (gemifloxacin, moxifloxacin, clindamycin, gentamycin, and streptomycin). Compounds 4 , 5 , 6 , and 7 showed high anti‐inflammatory activity compared with the standard drug indomethacin.     

新型胍基葡萄糖苷的合成及生物活性

将2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基异硫氰酸酯(1)与2-氨基-4/6-取代-苯并噻唑(2a~2e)反应, 生成糖基硫脲衍生物(3a~3e), 再在伯胺存在下经氯化汞脱硫, 得到一系列新的多乙酰基胍基糖苷类化合物(4a~4d, 5a~5d, 6a~6d, 7a~7d), 糖基的保护基团在甲醇钠/甲醇条件下脱除. 所有新化合物的结构均经IR, 1H NMR, MS谱和元素分析证实, 所得产物均为β-构型. 生物活性测试结果表明, 化合物4c, 6c, 8b, 8c等对HIV-1蛋白酶表现出了较高的抑制活性; 化合物7c具有抗流感乙型病毒活性; 化合物5e, 7c, 7d等对血管紧张素转化酶具有抑制活性.     

Synthesis of furo[3,2-g]chromones under microwave irradiation and their antitumor activity evaluation

A series of furo[3,2-g]chromone derivatives were synthesized via the reaction of furochromone carbaldehyde 1 with amines 3a - d and thioglycolic acid to give thiazolidinones 4a - d . The later react with benzaldehyde/thiourea or hydroxylamine and DMF-DMA in glacial acetic acid to give thiazolopyrimidines 5a - d or thiazoloisoxazoles 6a - d , respectively. Also, the synthesis of α-aminophosphonates via the one-pot reaction of 1 and amines 3a , b were trapped by dialkylphosphites 7a - c afforded the corresponding α-aminophosphonates 8a - f . Applying hexaalkyltriamidophosphites 9a , b to 1 gives alkylidenephosphorane ylides 11a , b in an open structure form. In the present investigation, the in vitro inhibition capacity of compounds ( 4a , 4c , 5b , 5c , 6b - d , 8a - f , and 11a ) was screened in three human cancer cell lines HCT-116, MCF-7, and HepG2. The anticancer activity results revealed that 8b and 8e had more potent cytotoxic inhibition activity against HCT-116 cell line; however, all the tested compounds had obviously less cytotoxic activity against MCF-7 cell line, while 5b , 5c , and 6d were potent against HepG2 cell line compared with that of doxorubicin.     

A novel synthesis of precocenes. Efficient synthesis and regioselective O-alkylation of dihydroxy-2,2-dimethyl-4-chromanones

The reactions of trihydroxybenzenes 1a-c and 3-methylbut-2-enoic acid ( 2 ) in a zinc chloride/water/phosphoryl chloride system afford either the new trihydroxyphenylbutenone derivatives 3b,c or dihydroxy-2,2-dimethyl-4-chromanones 4a-c in good yields. Compounds 3b,c can be cyclized in high yields to 4b,c in 5% sodium hydroxide solution. Regioselective O-alkylation of 4a-c leads to 5a-f in good yields. O-Alkylation of 5a-f , followed by reduction and dehydration, results in the formation of precocene 3 ( 7d ) and its regioisomer 7a-c,e,f . Methylation of 4a-c gives 6g-i . Subsequent reduction and dehydration affords precocene 2 ( 7h ) and its regioisomers 7g,i .     

Synthesis and Antimicrobial Studies of Novel Imidazole Containing Bisazetidinones and Bisthiazolidinone Derivatives

A simple, practical, and efficient approach to new series of imidazole containing bisazetidinones ( 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i , 7j and 9a , 9b , 9c , 9d , 9e , 9f , 9g , 9h , 9i , 9j ) was prepared by Staudinger [2 + 2] cycloaddition reaction, and bisthiazolidinones ( 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h , 8i , 8j and 10a , 10b , 10c , 10d , 10e , 10f , 10g , 10h , 10i , 10j ) were obtained by cyclization of bisimines with thioglycolic acid. The bisimines ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j and 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j ) were synthesized by the condensation of 3‐(1‐(3‐aminobenzyl)‐4, 5‐dihydro‐1H‐imidazol‐2‐yl) aniline ( 3 , 4 ) with a series of different substituted aromatic aldehydes. All the newly synthesized target compounds were evaluated for their in vitro antimicrobial activity against two Gram‐positive bacteria and two Gram‐negative bacteria. Additionally, these synthesized compounds were tested for their antifungal activities. Few compounds showed very good antibacterial and antifungal activity.     

Microwave assisted synthesis and unusual coupling of some novel pyrido[3,2-f][1,4]thiazepines

3-Amino-3-thioxopropanamide (1) reacted with ethyl acetoacetate to form 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (2), which reacted with α-haloketones 3 to produce 2,3-disubstituted-8-hydroxy-6-methyl-2H,5H-pyrido[3,2-f]-[1,4]thiazepin-5-ones 4a-c. Benzoylation of 4c led to the formation of the dibenzoate derivative 9. Compounds 4a-c could be prepared stepwise through the formation of S-alkylated derivatives 10a-c. Compounds 2, 4a-c, 9 and 10a-c were prepared using microwave as a source of heat, and gave better yields in shorter times than those achieved by traditional methods. Coupling of 4a-c with arenediazonium chlorides proceeded unusually to give the 6-hydroxy-4-methyl-2-(arylazo)thieno[2,3-b]pyridin-3(2H)-one ring contraction products 14. Structures of the newly synthesized compounds were proven by spectral and chemical methods.     

Exploration of quinoxaline derivatives as antimicrobial and anticancer agents

Novel 2 and 3‐substituted quinoxaline derivatives were synthesized through various synthetic pathways, among which cyanoacetamide and cyanoacetohydrazide quinoxaline derivatives 4a‐c and 11a‐c , respectively, were synthesized. Furthermore, methoxy quinoxaline derivatives 3c and quinoxaline derivatives bearing substituted pyridines 6a,b , 12a,b , and 13a,b were designed to be synthesized. However, we have synthesized acrylohydrazide 5a,b and 7 /acrylamide derivatives, Schiff base analogues 14a‐f , pyrazole derivatives 15a‐e, amide derivatives 16a‐f , guanidine derivatives 16 g,h as well as, quinoxalin‐2‐methylallyl propionate derivative 14g . All the synthesized compounds were confirmed via spectral data and elemental analyses. Moreover, the newly synthesized compounds were evaluated for their antimicrobial activity (Gm +ve, Gm ?ve in comparison to Gentamycin a standard) and fungi (in comparison to Ketoconazole as a standard). Thus, compound 16b showed promising antimicrobial activity against B. subtilis, P. vulgaris, and S. mutants with values ranging from 20 to 27‐mm zone of inhibition. While compounds 5a , 14e,f, and 16a,c,d,g,h showed potent antimicrobial activity. Moreover, the National Cancer Institute (NCI) selected 20 compounds that were submitted for anticancer screening against 60 types of cancer cell lines. The most active compounds are 5b and 12a where compound 5b containing 2,4‐dichlorophenyl moiety at cyanoacetamide linkage of hydrazine quinoxaline backbone exerted significant growth inhibition activity against Leukemia MOLT‐4, Renal cancer UO‐31, and Breast cancer MCF‐7. In addition, compound 12a having 4,6‐diaminopyridinone side chain at position‐3 of quinoxaline nucleus exhibited remarkable anticancer activity against renal cancer UO‐31.