Synthesis of some heterocyclic compounds derived from indole as antimicrobial agents

Recently, indoles are considered interesting heterocyclic compounds due to their wide range of biological activities such as antimicrobial activity. Herein, some new indole derivatives containing heterocyclic moieties were synthesized using 3-chloro-1H-Indole-2-carbaldehyde (1) as a starting material, then allowed to react with compounds containing active methylene under Knoevenagel condensation and afforded the corresponding compounds (2, 3, 9). Also, the compound (1) when allowed to react with hydrazine derivatives gave the corresponding thiosemiccarbazone, semicarbazone, and hydrazone derivatives (4, 5, 6). Reaction of thiosemicarbazone derivatives with α-halognated carbonyl compounds gave the thiazolyl indole derivatives (10, 12a–b). Cyclic chalcones (11a–c) were obtained when compound (10) reacted with different aromatic aldehydes. The structures of all new synthesized compounds were confirmed on the basis of spectral analysis, IR, 1H NMR, 13C NMR, and MS spectroscopy. All synthesized compounds were evaluated for their antimicrobial activity. Compounds (2, 5, 7, 8, 11a, 12a) showed high antibacterial activity and compounds (3, 6, 9, 10, 11a, 12a) showed high antifungal activity.     

Dodecanoyl isothiocyanate and N′-(2-cyanoacetyl) dodecanehydrazide as precursors for the synthesis of different heterocyclic compounds with interesting antioxidant and antitumor activity

Dodecanoyl isothiocyanate 1 was utilized for the construction of thioureido, 2-thioxo-2,3-dihydroquinazolin-4(1H)-one, benzo[d]-1,3-thiazin-4(H)-one and 3-amino quinazolin-4(3H)-one derivatives 2, 3, 4, and 5 respectively. However, N′-(2-cyanoacetyl) dodecanehydrazide 6 was also used as a key starting material for the construction of a variety of new pyrazolone, pyrazole, thiadiazole, pyridazine, chromeno[2,3-c]pyrazole, and dithiolane derivatives 7, 9, 12, 15, 18, and 20, respectively. The newly synthesized compounds were characterized by elemental analyses and spectral data (IR, ¹H NMR, and mass spectra). Some of the newly synthesized compounds bearing heterocyclic moieties were tested for antioxidant activity as reflected in their ability to inhibit oxidation in rat brain and kidney homogenates using 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) inhibition. Also, in vitro anticancer activity was examined using the standard (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) (MTT) method against a panel of two human tumor cell lines namely; hepatocellular carcinoma HepG2 and mammary gland breast cancer MCF-7. Compounds 12 and 16b exhibited the highest activities as antioxidant and antitumor agents. Meanwhile, compounds 7 and 20 showed moderate activities and the rest of the tested compounds showed weak activities.     

Studies on Spiroheterocycles,Part III: Synthesis of Diazaspiroundecanetetraone Derivatives Containing Biologically Active Heterocycles

Barbituric acid 2 upon Michael addition with dibenzal acetones 1a–c afforded the corresponding diazaspiro derivatives 3a–c . The base-catalyzed condensation of 3a–c with various aromatic aldehydes produces diarylidine derivatives 4a–l . The diarylidene compounds 4a–l on condensation with hydrazine, phenyl hydrazine, hydroxylamine, urea, guanidine carbonate, and hydrazine hydrate with acetic acid afforded their respective in situ oxidized products 5, 6, 7, 8, 9 , and 10 . The structures of the compounds are ascertained from their analytical and spectral data. Some of the compounds are screened for their biological activities against E. coli, B. cirroflagellosus, A. niger, and C. albicans.     

Modified Pyridine-Substituted Coumarins: A New Class of Antimicrobial and Antitubercular Agents

Some new biologically potent coumarin derivatives 7a–f, 8a–f, and 9a–f bearing modified pyridine moieties (indeno[1,2-b]pyridine, 4-azaphenanthrene and benzofuro [3,2-b]pyridine) at the sixth position were designed and synthesized. All the synthesized compounds were assayed for their antimicrobial efficiency against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi, Candida albicans, and Aspergillus niger. Most of the compounds showed appreciable antimicrobial activity against the tested strains. Compounds 8b, 8c, 9b, 9d, and 9f emerged as most proficient members of the series. The antitubercular activity for all the synthesized compounds was performed against Mycobacterium tuberculosis H37R_v. Compounds 8f, 9b, and 9f exhibited promising antitubercular activity. Consequently, synthesized derivatives were found to be worthy of further investigation.     

Convenient synthesis and anti-proliferative activity of some benzochromenes and chromenotriazolopyrimidines under classical methods and phase transfer catalysis

Abstract

A new series of benzochromene, benzochromenopyrimidine, and benzotriazolopyrimdine derivatives 3-10 were prepared via reaction of ethyl formimidate 2 with primary amines such as sulfanilamide, cyclohexylamine, 3-aminopyridine, 4-aminoantipyrine in addition to its reactions with different acid hydrazides. Compound 5 was further allowed to react with different C-electrophiles by classical and phase transfer catalysis conditions to get novel chromenotriazolopyrimidine derivatives. Screening of the antitumor activity in some of the newly synthesized compounds was tested in vitro against a panel of two human tumor cell lines namely HepG2 and HCT-116 cell lines. Compounds 4, 7, 8, 10, and 20 showed remarkable broad-spectrum antitumor activity.     

A new triterpenoid saponin and a diterpene glucoside from the seeds of Orychophragmus violaceus

One new triterpenoid saponin orychoside A (1) and one new diterpene glucoside orychoside B (12), together with eleven known compounds, were isolated from the seeds of Orychophragmus violaceus. The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The known compounds were identified by comparison with data reported in the literature. All compounds were tested for their cytotoxic activities against the HepG2 and A549 cell lines in vitro. The new compound 1 exhibited potent cytotoxicity against the two cell lines with IC₅₀ values of 7.13 and 8.77 μM, respectively. Compounds 2, 5, 8 and 9 were found to possess obvious cytotoxicity.     

Synthesis and antimicrobial evaluation of new 2-pyridinone and 2-iminochromene derivatives containing morpholine moiety

As trail to overcome on the antimicrobial drug-resistance problems, new functionalized 2-pyridinone and 2-iminochromene derivatives bearing morpholine moiety were designed and synthesized. The 2-pyridinone derivatives were obtained through the cyclization of cyanoacetohydrazone of 4-morpholinylacetophenone with 1,3-dicarbonyl compounds, α,β-unsaturated nitriles or 2-(arylidene)malononitriles. The 2-iminochromene derivatives were synthesized through the ring closure of cyanoacetohydrazonewith salicylaldehyde derivatives. The antibacterial and antifungal activities for the synthesized 2-pyridinone and 2-iminochromene derivatives were investigated. Most of the tested compounds showed moderate activity against P. vulgaris. Compounds 4a,b and 5a,b showed moderate activity against G −ve bacteria. All iminochromene derivatives showed moderate activity against C. albicans. Compound 8c was the most active compound.     

Dapson in Heterocyclic Chemistry,Part II: Antimicrobial and Antitumor Activities of Some Novel Sulfone Biscompounds Containing Biologically Active Thioureido,Carbamothioate, Quinazoline,Imidazolidine, and Thiazole Moieties

The reaction of 4,4′-diisothiocyanato-1,1-diphenylsulfone 2 with aromatic amines and phenol derivatives afforded the corresponding thioureio derivatives 3–9 , respectively. Also, the reaction of 2 with catechol gave the corresponding carbamothioate derivative 11. Quinazoline derivatives 14 and 15 were obtained in good yield via reaction of 2 with anthranlic acid derivatives. Imidazolidine biscompounds 16 and 17 were readily synthesized from the reaction of 2 with N-(4-substituted-phenyl)cyanothioformanilides. The structure of the products was confirmed from elemental analysis as well as spectral data. Most of the synthesized compounds showed remarkable antimicrobial activity compared with chloramphenicol and Grisofluvine as positive controls. Compound 6 was almost as active an antitumor agent as the reference drug Doxorubicin.     

Synthesis and evaluation of novel 4H-pyrazole and thiophene derivatives derived from chalcone as potential anti-proliferative agents,Pim-1 kinase inhibitors,and PAINS

The chalcone derivatives 3a-d reacted with either malononitrile or ethyl cyanoacetate in ethanol in the presence of catalytic amount of ammonium acetate in an oil bath at 120°C to give the Knowevenagel condensation products 5a-h . The latter compounds reacted with hydrazine hydrate and afforded the 4H-pyrazole derivatives 7a-h , respectively. The reaction of compounds 7a-h with ethyl cyanoacetate in dimethylformamide under refluxing condition afforded the cyanoacetamido derivatives 8a-h , respectively. When compounds 8a-h reacted with elemental sulfur and either of malononitrile or ethyl cyanoacetate in ethanol containing triethylamine, the thiophene derivatives 9a-h and 10a-h , respectively, were obtained. The structure of the newly synthesized compounds was established by the analytical and spectral data. All the newly synthesized compounds were evaluated against the six cancer cell lines: A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460. Compounds 3c , 5h , 7g , 7h , 8f , 9e , 9g , and 10g were selected to examine their Pim-1 kinase inhibition activity as these compounds showed high inhibition toward the c-Met kinase and the tested cancer cell lines. Furthermore, compounds 3b , 3c , 5g , 5h , 7f , 7g , 7h , 8e , 8f , 8g , 8h , 9e , 9f , 9g , 9h , 10g and 10h were selected to be tested for pan-assay interference compounds analysis (PAINS). Almost all the tested compounds showed zero PAINS alert and can be used as drug compounds in the future.     

2-Ethanethioamide in Heterocyclic Synthesis: Synthesis and Characterization of Several New Pyridine and Fused Azolo- and Azinopyridine Derivatives

Pyridine-2(1H)-thione derivatives 3a,b were synthesized from the reaction of 1-(phenyl-sulfanyl)acetone (1) and cinnnamonitrile derivatives 2a,b. Compounds 3a,b reacted with different halogenated reagents 7a–f to give 2-S-alkylpyridine derivatives 8a–l, which could be, in turn, cyclized into the corresponding thieno[2,3-b]pyridine derivatives 9a–l. Compounds 9d,j reacted with acetic anhydride, formic acid, carbon disulfide, phenyl isothiocyanate, and nitrous acid to yield the corresponding pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidine 12a,b, 15a,b, 17a,b, 20a,b, and pyrido[3′,2′:4,5]thieno[2,3-d][1,2,3]triazinone derivatives 22a,b, respectively.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Synthesis and fungicidal activity of 1,3,4-oxadiazol-2-yl thioether derivatives containing a phenazine-1-carboxylic acid scaffold

To find new higher fungicidal activities lead compounds and develop new eco-friendly agrochemicals, natural product phenazine-1-carboxylic acid (PCA) as scaffold, a series of 1,3,4-oxadiazol-2-yl thioether derivatives was synthesized and bio-assayed. The results reveal that most target compounds possessed moderate to good fungicidal activities against R. solani, S. sclerotioru and P. oryzac Cavgra. Compounds 6n and 6o exhibit more than 90% bioactivity against S. sclerotioru. The EC₅₀ value of compounds 6n and 6o are 11.16 and 30.47?μM respectively, in particular, compound 6n show equal activity against S. sclerotioru to PCA (10.49?μM). This result provides a valuable lead compound for further studies.     

Synthesis and antiproliferative activities of aminoalkylated polymethoxyflavonoid derivatives

A series of novel aminoalkylated polymethoxyflavonoid derivatives 3–11 was synthesised from 5-hydroxy-3,7,3′,4′-tetramethoxyflavonoid (1) through extending alkoxy chain at the 5-position, and introducing amine hydrogen bond receptor at the end of the side chain. Their antiproliferative activities were evaluated in vitro on a panel of three human cancer cell lines (Hela, HCC1954 and SK-OV-3). The results showed that all the target compounds exhibited antiproliferative activities against investigated cancer cells with IC₅₀ values of 9.51–53.33 μM. Compounds 5, 7, 8, 11 on Hela cells and compounds 4–9, 11 on HCC1954 exhibited more potency as compared to positive control cis-Platin.     

Synthesis and biological assessment of novel cyanopyridine derivatives

New pyridine derivatives bearing p-dimethyl amino phenyl and p-bromophenyl moieties at position-4 and 6 have been prepared. The behavior of pyridone derivative 2 toward ethyl chloroacetate followed by hydrazine hydrate gave pyridinyl acetohydrazide derivative 7, and its behavior toward carbon electrophiles has been investigated by its reaction with aromatic aldehydes, ethyl acetoacetate, acetyl acetone, cyclohexanone, phthalic anhydride, maleic anhydride, and isatin affording the pyridine derivatives 8a–e to 16, respectively. Treatment of compound 2 with acrylonitrile in Et₃N, yielded the N- alkylated derivative 17. Some pyrazole derivatives have been synthesized by interaction of the chalcone 1 with hydrazine hydrate afforded pyrazole derivative 18. Treatment of compound 18 with benzoyl chloride and or acetic anhydride resulted in the formation of the acylated compounds 19 and 20. Elemental and spectroscopic pieces of evidence characterized all the newly synthesized compounds. Some of the synthesized compounds were tested for their antibacterial activities against Gram-positive and Gram-negative bacteria.     

Synthesis and characterization of new 4,5-dihydropyrazol-1-yl derivatives

In this study, first, a series of chalcone compounds S1–S6 were synthesized from various acetophenone derivatives (acetophenone, p-methyl acetophenone, and p-methoxy acetophenone) and aromatic aldehyde derivatives (benzaldehyde, p-methyl benzaldehyde, and p-methoxy benzaldehyde) by the Claisen–Schmidt condensation reaction. These S1–S6 compounds were then used in the preparation of 4,5-dihydropyrazol-1-yl derivatives S7–S15. Finally, four new compounds S16–S19 were synthesized from compound (S7, S8, S9, and S12) and 2,4-dinitrophenylhydrazine. Therefore, three known and ten new heterocyclic compounds were synthesized and completely characterized using ¹H NMR, ¹³C NMR, IR, and elemental analysis.     

Synthesis of novel triazolothione,thiadiazole, triazole-functionalized furo/thieno[2,3-b]pyridine derivatives and their antimicrobial activity

A series of novel triazolothione, thiadiazole, triazole-functionalized furo/thieno[2,3-b]pyridine derivatives 9a–l, respectively, were prepared starting from 2 (1H) pyridone 3 through selective O/S-alkylation followed by Thorpe–Ziegler cyclization to form furo/thieno[2,3-b]pyridine derivatives 6. Compounds 6 on reaction with hydrazine hydrate resulted carbohydrazide derivatives 7 and further reacted with diverse substituted phenyl isothiocyanates to form phenyl hydrazine carbothiamide derivatives 8. Each compound 8 is independently reacted in presence of NaOH, H₂SO₄, and N₂H₄.H₂O to form triazolothione, thiadiazole, triazole-functionalized furo/thieno[2,3-b]pyridine derivatives 9a–l, respectively. All the products 9a–l were screened against Gram +ve, Gram –ve bacteria and fungal strains. Compounds 9c–h showed high activity against Bacillus subtilis microbial-type culture collection (MTCC) 121 at <8.0 micromolar concentration. Promising compounds further screened for minimum bactericidal concentration against B. subtilis MTCC 121 using ciprofloxacin as standard and found to show very good activity. These compounds also screened for biofilm inhibition activity against B. subtilis MTCC 121 using erythromycin as standard and confirmed the high activity.     

Synthesis and biological evaluation of new 3,5-di(trifluoromethyl)-1,2,4-triazolesulfonylurea and thiourea derivatives as antidiabetic and antimicrobial agents

Fluorinated 1,2,4-triazoles 3 and benzenesulfonyl urea and thiourea derivatives as well as their cyclic sulfonylthioureas 4–10 were prepared as antimicrobial agents. The chemistry involves the condensation of sulfanilamide derivatives 1 with trifluoroacetic anhydride to give N-di(trifluoroacetyl)sulfonamides 2 which upon reaction with hydrazine hydrate afforded the corresponding triazole derivatives 3. Reaction of triazole derivative 3a with isocyanates and isothiocyanates gave the corresponding ureas 4 and thioureas 5. Cyclization of thiourea derivatives with ethyl bromoacetate, 1,2-diiodoethane, diethyl oxalate and α-bromoacetophenone derivatives yielded the corresponding 4-oxothiazolidines 7, thiazolidines 8, 4,5-dioxothiazolidines 9 and thiazolines 10. Preliminary biological screening of the prepared compounds revealed significant antimicrobial and mild antidiabetic activities.     

5-Anthracenylidene and 5-(4-Benzyloxy-3-methoxy)benzylidene-hydantoin and 2-Thiohydantoin Derivatives,Synthesis, and S-Alkylation

Abstract

5-Anthracenylidene- and 5-(4-benzyloxy-3-methoxy)benzylidene-hydantoin and 2-thiohydantoin derivatives 3a-g were prepared by condensation of anthracene-9-carboxaldehyde and 4-benzyloxy-3-methoxybenzylaldehyde with hydantoin and 2-thiohydantoin derivatives. Compounds 3a, b, f undergo Mannich reaction with formaldehyde and morpholine to give the corresponding Mannich products 4a–c. For the synthesis of alkylmercaptohydantoin 5a–o, the potassium salt of compounds 3a, b, e, f were reacted with an alkylhalide, either methyl iodide, phenacyl bromide, ethyl bromo acetate, allyl bromide, or methallyl bromide, under stirring at room temperature to afford the alkylmercaptohydantoins 5a–o. Acid hydrolysis of compounds 5a–c afforded the corresponding arylidene-hydantoin derivatives 3c, d, g. 2-Methylmercapto-hydantoin derivatives 5a, c were reacted with some secondary amines such as morpholine or piperidine to afford 5-(4-benzyloxy-3-methoxy)benzylidene-2-morpholino- or piperidino glycocyamidine derivatives 7a, 5-anthracenylidene-2-morpholin-, or piperidino glycocyamidine derivatives 7b, c.

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GRAPHICAL ABSTRACT     

Synthesis and Antimicrobial Activity of Some New Heterocyclic Schiff Bases Derived from 2-Amino-3-formylchromone

Some new hydrazone derivatives 3a–e have been obtained from 2-amino-3-formylchromone (1). Heterocyclization of thiocarbohydrazone derivative 3e via reaction with some electrophilic reagents afforded 1,2,4-triazoles 6–8 and 1,2,4-triazines 9–13. Condensation reactions of aldehyde 1 with o-aminoaldehydes and/or ketones afforded some new isolated and condensed heterocyclic systems 17, 19, and 20. The newly synthesized compounds were screened for their antimicrobial activity.     

Studies of Thiazolopyridines,Part 6: Synthesis and Antimicrobial Evaluation of Some Novel Thiazolo[3,2-a] Pyridine and Thiazolo[2′,3′:6,1]-pyrido[2,3-d]pyrimidine Derivatives

Condensation of thiazolinone 1 with aromatic aldehydes yielded the corresponding methylidene derivatives 2a–f. Cyclization of compounds 2a–f with arylidenemalononitrile 3 (1:1 molar ratio) in ethanol in the presence of piperidine furnished the novel thiazolo[3,2-a]pyridines 5a–v, via Michael adduct 4. Compounds 5p, r were cyclized with malononitrile in the presence of piperidine to yield thiazolo[3,2-a][1,8]naphthryidines 7a, b. Thiazolo-[2′,3′:1,6]pyrido[2,3-d]pyrimidine 9a–cwere obtained by cyclization of compounds 5c, p, r with formic acid. The structure of the synthesized compounds was established by analytical and spectral data. Also, some of the synthesized compounds were screened for antimicrobial activity in vitro.     

Click synthesis of new 7-chloroquinoline derivatives by using ultrasound irradiation and evaluation of their biological activity

This study describes the click synthesis of new 7-chloroquinoline derivatives by using ultrasound irradiation and evaluation of their activity as antimicrobial, antimalarial and the anticancer. All the compounds show moderate antimalarial activity with IC₅₀?<?100?μM, six of them showed high antimalarial activity (2, 3, 4, 6, 8 and 9) with IC₅₀?<?50?μM. The most active 7-chloroquinoline derivative is a compound (9). Also, the newly synthesized compounds were screened for their antitumor activity towards three lines of cancer cells, MCF-7 (human breast cancer), HCT-116 (colon carcinoma) and Hela (Cervical carcinoma) cell lines. Compounds (3) and (9) exerted the highest activity on all cell lines and showed special selectivity toward MCF-7 cells and the antibacterial screening data showed moderate to good inhibition zone (12.5?±?0.63–23.8?±?1.5) towards all the tested compounds. Elucidation of the structures of these new pure compounds was based on, IR, ¹H NMR, ¹³C NMR, MS and their elemental analysis.