Synthesis and Anticancer Evaluation of Some Novel Thiophene,Thieno[3,2‐d]pyrimidine,Thieno[3,2‐b]pyridine,and Thieno[3,2‐e][1,4]oxazepine Derivatives Containing Benzothiazole Moiety

In an attempt to establish novel candidate with promising anticancer activity, two derivatives of (benzo[d]thiazol‐2‐yl)thiophene backbone 1 and 14 were synthesized, and they further reacted with various chemical reagents to afford the corresponding substituted thiophene derivatives 6 , 8 , 10 , 15 , 17 , and 20 , thieno[3,2‐d]pyrimidine derivatives 2 – 5 , 7 , 9 , 16 , 21 , 23 , and 24 , thieno[3,2‐b]pyridine derivatives 11 – 13 , and thieno[3,2‐e][1,4]oxazepine derivative 18 . Structures of prepared compounds were affirmed via spectral and elemental data. Among the obtained compounds, seven derivatives 2 , 3 , 4 , 5 , 11 , 12 , and 13 were chosen by National Cancer Institute, USA. Such compounds were screened for their antitumor activity versus 60 cancer cell lines in one‐dose (10 μmol) screening assay. The outcomes showed that all selected compounds exhibited moderate to high anticancer activity towards many cancer cell lines among which compounds 5 and 11 exerted potent antitumor activity against numerous malignant growth cell lines particularly Ovarian Cancer IGROV1.     

Heterocyclic synthesis via enaminones: Novel synthesis of (1H)‐pyridin‐2‐one,pyrazolo[1,5‐a]pyrimidine and isoxazole derivatives incorporating a N‐methylphthalimide and their biological evaluation

Novel synthesis of (1H)‐pyridin‐2‐one, pyrazolo[1,5‐a]pyrimidine and isoxazole derivatives incorporating N‐methylphthalimide moiety are reported. Reaction of enaminone 2 with malononitrile affords 4. Condensation of 2 with cyanothioacetamide or benzoylacetonitrile affords compounds 6 and 7 respectively. Reaction of 2 with hydrazine hydrate afford 2,3‐dihydrophthalazine‐1,4‐dione ( 10 ). Condensation of 2 with hydroxylamine and 3‐aminopyrazole derivatives affords compounds 12 and 15a,b respectively. Antimicrobial and antifungal activity were determined for representative compounds and most of them showed moderate activity as antimicrobial agents, while compounds 2 and 7 show strong activity against Aspergillus niger. The structure of the newly synthesized compounds was elucidated by elemental analyses and ¹H nmr spectra and some cases by ¹³C nmr investigation.     

Synthesis,Antimicrobial Activity and Molecular Modeling of Some Novel 5‐Aminopyrazole,Pyrazolo[1,5‐a]pyrimidine,Bispyrazole and Bispyridone Derivatives Containing Antipyrinyl Moiety

2‐Cyano‐N‐(antipyrin‐4‐yl)‐3‐(ethylthio)‐3‐(naphthalen‐1‐ylamino)acryl‐amide 4 was achieved via a one‐pot, three‐component reactions of cyanoacetamide derivative 2 , 2‐naphthyl isothiocyanate, and diethyl‐sulphate. The cyano acrylamide derivative 4 was hydrazinolysis to furnish 5‐aminopyrazole 5 ; many pyrazolo[1,5‐a ]pyrimidines 10a,b, 14, 15, 16, 18, and 20 have been synthesized via treatment of 5 with some electrophilic reagents. Also, ternary condensation of cyanoacetamide derivative 2 , terephthalaldehyde, and active methylene derivatives afforded bispyridone derivatives 21a,b . The structures of the new compounds were confirmed on the basis of elemental analysis and spectral data. Representative compounds of the synthesized products were tested and evaluated as antimicrobial. In general, the novel‐synthesized compounds showed a good antimicrobial activity against Gram‐positive bacteria, Gram‐negative bacteria, and antifungal activity against Azithromycin and Ketoconazole . The molecular modeling of the 21a and 21b as representative examples of the synthesized compounds has been drawn, and their molecular parameters were calculated.     

Synthesis and antimicrobial activity of new C‐furyl glycosides bearing substituted 1,3,4‐oxadiazoles

New 2,5‐disubstituted 1,3,4‐oxadiazole derivatives bearing C‐furyl glycoside moieties and their sugar hydrazone as well as their per‐O‐acetyl derivatives were synthesized starting from ethyl 2‐[5‐(3,4‐dihydroxytetrahydrofuran‐2‐yl)‐2‐methylfuran‐3‐yl]‐2‐oxoacetate. Heterocyclization of the sugar hydrazones using acetic anhydride afforded the corresponding oxadiazoline acyclic C‐nucleosides. The antimicrobial activity evaluation showed that many of the synthesized compounds revealed moderate to high antimicrobial activity. J. Heterocyclic Chem., (2011)     

Synthesis of Some Novel Pyrazole‐Substituted 9‐Anilinoacridine Derivatives and Evaluation for their Antioxidant and Cytotoxic Activities

This article focuses on the synthesis of new series of pyrazole‐substituted 9‐anilinoacridine derivatives 5a – m and 6a – l . The compounds were confirmed by physical and analytical data. The synthesized compounds when screened for in vitro antioxidant activity showed promising activity for many compounds. The selected compounds were screened for cytotoxic activity showed promising inhibition of HEp‐2 cell line for the compounds 6c , 6e , and 6f .     

Synthesis and Antimicrobial Evaluations of Some Novel Mono‐, Bis‐, and Tris‐Nitro‐1,2,4‐Triazines

Substituted‐1,2,4‐triazines were conveniently synthesized in one pot by the cyclization of arylnitroformaldehyde hydrazone derivatives 1 and 5 with different primary amines in ~37% formaldehyde solution. The synthesized compounds were arranged into novel mono‐, bis‐, and tris‐nitro‐1,2,4‐triazine derivatives 2 , 3 , 4 , 6 , and 7 . The antibacterial and antifungal activity of the synthesized compounds were screened against bacterial strains Escherichia coli (as Gram − ve) and Staphylococcus aureus (as Gram + ve), and fungal strains Aspergillus flavus and Candida albicans . All the synthesized compounds exhibit various patterns of inhibitory activity on the two pathogenic bacterial strains. However, the same compounds showed no activity against the tested fungal strains.     

Biological Evaluation of Some Antimicrobial Nano‐Materials

N‐(benzothiazol‐2‐yl)‐2‐(piperidin‐1‐yl)acetamide derivatives ( 1‐24 ) were obtained by the reaction of 2‐chloro‐N‐(benzothiazole‐2‐yl)acetamides with piperidine derivatives. The structures of the compounds were elucidated by ¹H‐NMR and mass spectral data and elemental analysis. The compounds were screened for their antimicrobial activities against pathogenic bacteria and Candida species. The compounds were also investigated for their cytotoxic properties using MTT assay. The microbiological results revealed that the compounds were more effective against fungi than bacteria. Among Candida species, C. utilis was the most susceptible fungus to compounds 7 and 11 . It is apparent that 2,6‐dimethylpiperidine group and chloro and methyl substituents on benzothiazole ring have an important impact on anticandidal activity. MTT assay indicated that the effective doses of these derivatives were lower than their cytotoxic doses.     

New Synthetic Approaches for Cytotoxic Activity of Novel 1,8‐Naphthyridine Derivatives

A series of substituted 1,8‐naphthyridine derivatives was synthesized as cytotoxic agent by using starting material 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carbohydrazide ( 1 ). Further reactions on compound 1 were processed with different reagents to afford the corresponding 3‐heteraryl‐1,8‐naphthyridine derivatives 2–22 . In vitro cytotoxic activities of new synthesized compounds were assayed against Ehrlich ascites carcinoma, which showed that compounds 3 and 12 had the more potent cytotoxic activity.     

Synthesis and Biological Activity of 3‐Methyl‐1H‐pyrazole‐4‐carboxylic Ester Derivatives

In search of novel pyrazole derivatives with bioactivity, a series of 3‐methyl‐1H‐pyrazole‐4‐caboxylic: ester derivatives were synthesized via α‐oxoketene dithioacetals as starting material. The structures of all compounds prepared were confirmed by ^lH NMR, IR, MS and elemental analyses. Preliminary bioassays indicated that some compounds showed fungicidal activity against wheat rust, phoma asparagi and antiviral activity against TMV.     

Synthesis of New PMB‐Substituted Indoles Containing 1,3,4‐Oxadiazole and 1,2,4‐Triazole Units

A series of new indolyl‐1,3,4‐oxadiazole derivatives 3 , 4 , 5 , 6 , 7 and 10 , indolyl‐1,2,4‐triazole derivatives 14 and 15 was prepared, using 1‐(4‐methoxybenzyl)‐1H‐indole‐3‐carbohydrazide ( 2 ) as a key intermediate. Some of the new compounds were evaluated for their antineoplastic activity.     

Synthesis and Antimicrobial Evaluation of Novel Derivatives of Semicarbazide and 1,2,4‐triazole

Reaction of phenoxyacetic acid hydrazide with isocyanate was used to the synthesis of new semicarbazide derivatives. Cyclization of these compounds in a 2% aqueous solution of sodium hydroxide led to formation of 1,2,4‐triazole‐3‐one. The chemical structure of synthesized compounds was confirmed by elemental analysis and spectroscopic methods (¹H and ¹³C NMR). On the basis of the NMR, spectra were found that cyclic compounds 1,2,4‐triazole exist in the ‐one form. Moreover, all derivatives were examined for their in vitro activity against some species of bacteria. New compounds presented mild or moderate antimicrobial activity only against reference Gram‐positive bacteria. Two derivatives (one semicarbazide and one triazole) showed bactericidal or bacteriostatic activity.     

Novel Steroidal (6R)‐Spiro‐1,3,4‐thiadiazoline Derivatives as Anti‐bacterial Agents

Novel steroidal (6R)‐spiro‐1,3,4‐thiadiazoline derivatives have been synthesized by the cyclization of steroidal thiosemicarbazones. Thiosemicarbazones have been synthesized by the reaction of steroidal ketones with thiosemicarbazide. All the compounds have been characterized by IR, ¹H NMR, mass and elemental analyses. The antibacterial activities of these compounds have been first tested in vitro by the disk diffusion assay against two Gram‐positive and two Gram‐negative bacteria, and then the minimum inhibitory concentration (MIC) values have been determined with the reference of standard drug amoxicillin. The results showed that steroidal thiadiazoline derivatives exhibited better antibacterial activity than the steroidal thiosemicarbazone derivatives. Chloro and acetoxy substituents on the 3β‐position of the steroidal thiadiazoline ring increased the anti‐bacterial activity. Among all the compounds, compounds 7 and 8 were found better inhibitors as compared to the respective drug amoxicillin.     

An Efficient Synthesis of Novel 2‐(5‐indolyl)‐1H‐benzimidazole Derivatives and Evaluation of Their Antimicrobial Activities

In this paper, we report the synthesis of novel 2‐(5‐indolyl)‐1H‐benzimidazole derivatives. The methodology involves the Sonogashira reaction of 4‐(1H‐benzimidazol‐2‐yl)‐2‐bromo‐N,N‐dimethylaniline ( 3 ) with variety of terminal alkynes to get corresponding novel 4‐(1H‐benzimidazol‐2‐yl)‐2‐alkynyl‐N,N‐dimethylaniline derivatives ( 4 ). These compounds on iodocyclization afforded novel iodoindolylbenzimidazole derivatives ( 5 ). The resulting compounds were functionalized further via palladium‐mediated carbon–carbon bond formation for generating novel structurally diversified heterocyclic compounds. All these newly synthesized compounds were evaluated for antimicrobial activity.     

Design,Synthesis, and Antifungal Evaluation of Novel Benzoxazole Derivatives Containing a 1,2,3‐Triazole Moiety

For finding novel bioactive compounds with significant antifungal activities, 17 novel benzoxazole derivatives containing a 1,2,3‐triazole moiety were synthesized by the copper(II) acetylacetonate‐catalyzed cyclization reaction between 2‐aminophenol derivatives and 1H‐1,2,3‐triazole‐4‐carbaldehyde derivatives ( 4a ), which were prepared through three steps using aromatic amine as the starting material. Antifungal activities of the prepared compounds were evaluated against Botrytis cinerea (BC) and Fusarium Verticillium (FV). The test results indicated that compounds 5b , 5c , 5h, and 5n show good inhibitory effects on fungi. The preliminary structure–activity relationship is also discussed.     

Synthesis,Docking, ADME‐Tox Study of 2‐(2‐(2‐Chlorophenyl)quinoline‐4‐carbonyl)‐N‐substituted hydrazinecarbothioamide Derivatives and Their Biological Evaluation

A series of 2‐(2‐(2‐chlorophenyl)quinoline‐4‐carbonyl)‐N‐substituted hydrazinecarbothioamide derivatives were synthesized by facile and efficient conventional method. The structures of the compounds were elucidated with the aid of an elemental analysis, IR, ESI‐MS, ¹H‐NMR, and ¹³C‐NMR spectral data. The synthesized compounds were evaluated for their in vitro antibacterial, antifungal, antimalarial, and antituberculosis activity against standard drugs. The bacterial studies were determined against gram‐positive and negative bacteria. These compounds were found to a broad spectrum of activity against the screened bacteria, but poor activity was observed against Pseudomonas aeruginosa and Escherichia coli. Compounds 8d , 8f , 8i , 8l , and 8n showed the potent activity against Staphylococcus aureus. Compounds 8d , 8g , 8k , 8l , and 8q show the potent activity against antimalarial as compared with the standard drugs Chloroquine, Quinine and compounds 8h , 8n , and 8o shows mild activity against H37Rv strain. Molecular docking revealed that synthesized derivatives and target proteins were actively involved in a binding pattern and had a significant corelation with biological activity. We have also performed a molecular dynamics and ADME‐Tox parameters for the synthesized compounds.     

Synthesis and In Vitro Antibacterial Activity of Novel Steroidal (6R)‐Spiro‐1,3,4‐thiadiazoline Derivatives

Novel steroidal (6R)‐spiro‐1,3,4‐thiadiazoline derivatives were synthesized by the cyclization of steroidal thiosemicarbazones with acetic anhydride, screened in vitro against antibacterial activity using disc‐diffusion method and the minimum inhibitory concentration. The results showed that steroidal thiadiazoline derivatives exhibited better antibacterial activity than the steroidal thiosemicarbazone derivatives. Chloro and acetoxy substituents on the 3β‐position of the steroidal thiadiazoline ring increased the antibacterial activity. Among all the compounds, compound 7 and 8 were found better inhibitors of both types of bacteria (Gram‐positive and Gram‐negative) as compared to the respective drug amoxicillin. All the synthesized compounds were well characterized by spectroscopic methods such as IR, ¹H‐NMR, ¹³C‐NMR mass, and elemental analysis and their stereochemistry was also discussed.     

Studies on pyrazine derivatives LII: Antibacterial and antifungal activity of nitrogen heterocyclic compounds obtained by pyrazinamidrazone usage

Using reactivity of pyrazinamidrazones and their N′‐substituted derivatives 1–8 in reaction with sulfonyl chlorides sulfone derivatives 9–17 were obtained, with orthoformate cyclized to sulfonyl compounds 18–20 . Amidrazones in reaction with pyraziniminoesters gave dihydrazidines 21–23 , which cyclized to 3,5‐dipyrazine derivatives of 1,2,4‐triazole 24–26 . 1‐Methyl‐ or 1‐phenyl‐3‐pyrazine‐1,2,4‐triazole 27–38 was formed in reaction of amidrazones 1–8 with orthoformate and orthoacetate or benzoyl chloride. N′‐Phenylamidrazones 3, 8 in reaction with thionyl chloride were transformed to 1,2,3,5‐thiatriazole S‐oxides 39, 40 . Obtained compounds exhibited low antibacterial activity. Antifungal activity was affirmed for compounds 1, 3, 4, 5, 8, 37, 39, and 40 , for which minimal inhibitory concentration (MIC) was in the concentration range of 16–128 μg/mL. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:49–58, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20751     

Design,Synthesis, and Anticancer Activity of New Oxadiazolyl‐Linked and Thiazolyl‐Linked Benzimidazole Arylidines,Thioglycoside, and Acyclic Analogs

2‐[(4‐Thiazolylmethyl)thio]‐1H‐benzimidazole 3 was prepared and was allowed to react with ethyl chloroactate then with hydrazine hydrate to afford the hydrazide derivative 5 , which was then reacted with aromatic aldehydes to afford the corresponding arylidine derivatives 6 – 9 . Heterocyclization of the latter hydrazones with acetic anhydride afforded the substituted 1,3,4‐oxadiazoline derivatives 10 – 13 . In addition, new ((thiazolyl)imidazolyl) oxadiazole thioglycoside and acyclic‐C nucleoside analog were prepared via heterocylization of the hydrazide 5 then glycosylation with α‐acetobromoglucose or condensation with D‐xylose, respectively. All the new compounds were structurally characterized. The anticancer activity of some of the newly synthesized compounds was studied against human breast cancer cells (MCF‐7). The results of the anticancer activity showed that compounds 8 , 11 , 12 , 17 , and 18 revealed high activities superior to Doxorubicin; however, the other derivatives showed moderate to low inhibition activities against human breast cancer cells. Docking studies into CDK2 enzyme were investigated, which supported the anticancer activity results.     

Efficient Synthesis of New Benzofuran‐based Thiazoles and Investigation of their Cytotoxic Activity Against Human Breast Carcinoma Cell Lines

A new series of 1,3‐thiazole‐benzofuran derivatives was synthesized via heterocyclization of 2‐(1‐(6‐alkoxy‐4,7‐dimethoxybenzofuran‐5‐yl)ethylidene)‐2‐methyl‐2l4‐diazane‐1‐carbothioamides with hydrazonoyl halides. Also, 1‐(4,7‐dimethoxybenzofuran‐5‐yl)‐3‐phenylprop‐2‐en‐1‐one derivatives were used for synthesis of another series of 1,3‐thiazole‐pyrazole‐benzofuran. The structure of the newly synthesized products was elucidated via elemental analysis, spectral data, and alternative routes whenever possible. Seven new compounds were evaluated for their anticancer activity against the human breast carcinoma (MCF‐7) cell lines compared with doxorubicin drug. The results revealed that some new compounds showed promising anticancer activity.