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Various substituted synthetic chalcones demonstrated potent anti-cancer activities.

Background Thiazole and thiosemicarbazone derivatives are known to have potential anticancer activity with a mechanism of action related to inhibition of matrix metallo-proteinases, kinases and anti-apoptotic BCL2 family proteins. Materials and methods A novel three series of 5-(1-(2-(thiazol-2-yl)hydrazono)ethyl)thiazole derivatives were prepared in a one-pot three-component reaction using 2-(2-benzylidene hydrazinyl)-4-methylthiazole as a starting precursor. MS, IR, 1H-NMR and 13C-NMR were used to elucidate the structures of the synthesized compounds. Most of the synthesized products were evaluated for their in vitro anticancer screening against HCT-116, HT-29 and HepG2 using the MTT colorimetric assay. Results The results indicated that compounds 4c, 4d and 8c showed growth inhibition activity against HCT-116 with IC50 values of 3.80 ± 0.80, 3.65 ± 0.90 and 3.16 ± 0.90 μM, respectively, compared to harmine (IC50 = 2.40 ± 0.12 μM) and cisplatin (IC50 = 5.18 ± 0.94 μM) reference drugs. Also, compounds 8c, 4d and 4c showed promising IC50 values of 3.47 ± 0.79, 4.13 ± 0.51 and 7.24 ± 0.62 μM, respectively, against the more resistant human colorectal cancer (HT-29) cell line compared with harmine (IC50 = 4.59 ± 0.67 μM) and cisplatin (IC50 = 11.68 ± 1.54 μM). On the other hand, compounds 4d, 4c, 8c and 11c were the most active (IC50 values of 2.31± 0.43, 2.94 ± 0.62, 4.57 ± 0.85 and 9.86 ± 0.78 μM, respectively) against the hepatocellular carcinoma (HepG2) cell line compared with harmine (IC50 = 2.54 ± 0.82 μM) and cisplatin (IC50 = 41 ± 0.63 μM). The study also suggested that the mechanism of the anticancer action exerted by the most active compounds (4c, 4d and 8c) inside HCT-116 cells was apoptosis through the Bcl-2 family. Conclusion Thiazole scaffolds 4c, 4d and 8c showed anticancer activities in the micromolar range and are appropriate as a candidate for cancer treatment.

Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo[2,3-d]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance to the structure–activity relationship (SAR) studies of known PI3K-α inhibitors, different linkers including amide, urea and ether were attached to a piperazinyl furo[2,3-d]pyrimidine core. The synthesized compounds that revealed moderate PI3K-α inhibitory activity were tested for their anti-proliferative activities against pancreatic carcinoma on the PANC-1 cell line. Compounds 7b and 8a showed the highest anti-proliferative activity with IC50 values of 4.5 μM and 6 μM, respectively and relatively, the best in vitro PI3K inhibition ability within the newly synthesized compounds. Additionally, all the newly synthesized final compounds were tested on 60 human cancer cell lines. A docking study was carried out on the PI3K-α active site showing a comparable binding mode to that of FDA approved PI3K-α inhibitors. These newly discovered lipid kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agents.

Background: Several biologically active indole alkaloids have been isolated from marine organisms over the previous few years. Many scientsts interested in synthesis of the marine azepinoindole alkaloids due to their wide range of bioliogical activies. Objective: We interested herein to synthesize a new series of some analogues of new naturally occurring azepinoindole alkaloids. Method: A novel series of [1,2,4,5]tetrazepino[6,7-b]indoles, Marine natural product Hyrtioreticuline C and D analogues, were synthesized via the reaction of 3-hydrazonoindolin-2-one with hydrzaonoyl chlorides in basic medium. Results: The spectral data of the products proved their structure. All new derivatives were tested against two carcinoma cell lines ((A-549 & HepG2)) in comparison with the well-known anticancer standard drug (cisplatin) and two derivatives from the tested compounds showed activity more potent than the reference drug. Conclusion: We succeeded in synthesis of new antitumor active azepinoindole alkaloids.

Background: A novel series of fused imidazole was prepared from the reaction of 2- bromoacetyl-3-phenyl-1,3,4-thiadiazole with various heterocyclic amines under microwave irradiation. The structures of all the novel products were elucidated based on the elemental analysis and spectral data. Results: In addition, the biological activity of the newly synthesized compounds was evaluated and the results obtained indicate their potency as anti-inflammatory, analgesic and anti- ulcer agents. Conclusion: The binding mechanism of the most active compounds was studied using MOE to analyze the molecular interactions.

2-Bromoacetyl-3-phenyl-1,3,4-thiadiazole derivative was synthesized and reacted with a number of heterocyclic amines to give a series of fused imidazole derivatives. Also, reaction of 2-bromoacetyl-3-phenyl-1,3,4-thiadiazole with o-phenylene diamine and 2-aminothiophenol yielded the respective products. Moreover, reaction of 2-bromoacetyl-3-phenyl-1,3,4-thiadiazole with thiourea, thiosemicarbazide, thiocarbahydrazide gave the respective thiazoles. The structures of all the novel products were elucidated on the basis of elemental analysis and spectral data. In addition, the biological activity of the newly synthesized compounds was evaluated, and the results obtained indicate their potency as anti-inflammatory, analgesic, and anti-ulcer agents. The binding mechanism of the most active compounds was studied using MOE to analyze the molecular interactions.

The current review presents recent progress in the utility of N,N-dimethyl enaminones as building blocks for a diverse range of acyclic, carbocyclic, five- and six-membered heterocyclic a broad range of heterocyclic and fused heterocyclic derivatives. Most importantly, these N,N-dimethyl analogues have proven to be of biological interest and provide an access to new class of biologically active heterocyclic compounds for biomedical applications. All of these topics are drawn from the recent literature till 2016.

A series of new pyrazolone and pyrazole derivatives with expected antifungicidal activity have been prepared through the reactions 3-phenyl-1-H-pyrazol-5(4H)-one (3) and 4-(dimethylaminomethylene)-3-phenyl-1H-pyrazol-5(4H)-one (5) with a variety of electrophilic reagents and nucleophilic reagents. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral studies.

In the reaction of 2-amino-3-carbethoxythiophene derivative 2b with hydrazine hydrate the respective aminocarbohydrazide 3 was isolated. Treatment of the latter product with carbon disulfide in alkaline medium caused a heterocyclization to give 1,3,4-oxadiazole-2-thione 5 rather than 3-amino-2-thioxothieno[2,3- d ]pyrimidin-4-one 4 , which could be obtained on treatment of carbohydrazide 3 with thiourea. The structure of products 4 and 5 was proved by spectroscopic methods and chemical transformations. Derivatization led to two novel series of condensed and uncondensed thiophenes, which were of significant interest for biological study. Since compound 4 contains two adjacent reactive functional groups, it reacted readily with different electrophilic reagents to provide a series of thieno[2,3-d]pyrimidin-4-one derivatives with annelated bridgehead nitrogen heterocycles 8 - 11 , whereas a second series of 3-heteroaryl-substituted thiophenes 13 - 17 was obtained by thioamide functionalization in 1,3,4-oxadiazole derivative 5 using various chemical reagents. The new thiophene-based derivatives were evaluated for their preliminary antimicrobial activity against a representative panel of Gram-positive and Gram-negative bacteria as well as fungi strains. The compounds tested displayed different levels of inhibitory effects, with the assays carried out on two pathogenic bacteria and two pathogenic fungi. Of these compounds, the monocyclic aminothiophene derivative 15 showed the highest effect on pathogenic bacteria, while the tricyclic condensed thiophene derivative 8 was observed to have the same inhibitory effect against pathogenic mould ( Aspergillus flavus ) as the reference drug Amphotericin B. For those derivatives belonging to first series of condensed thiophenes with annelated bridgehead nitrogen heterocycles, it has been observed that the antibacterial effect was in general found to be significantly higher than the corresponding uncondensed analogues. Although most of the condensed and uncondensed thiophenes under investigation showed generally remarkable in vitro antibacterial activity, unfortunately, no significant antifungal activity was observed with any of the compounds tested except for 8. Surprisingly, compound 8 displayed an excellent effect on fungus ( A. flavus ) on the one hand, whereas the lowest effect on bacteria on the other. The attachment of a triazolothiadiazine moiety to a thiophene ring could be considered as a promising strategy for the development of new therapeutic antibacterial agents related to the aminothiophene system.

In the search for new therapeutic agents against microbial infections, two novel series of monocyclic and tricyclic 5-(phenylazo)thiophene systems were synthesized based on 3-amino-2-thioxopyrimidinone and 2-cyanoacetamidothiophene derivatives 4 and 6. Functionalization of the pyrimidine ring in precursor 4 resulted in the formation of the target tricyclic condensed thiophenes 7, 12, and 13a, b, by the application of a variety of addition, substitution, and condensation reactions. On the other hand, derivatization of the versatile cyanoacetylated compound 6 led to a second series of monocyclic N-substituted aminothiophenes 15, 17, 19, and 20, through convenient methods. The new thiophene-based derivatives were tested for their antimicrobial activity with reference to relevant standard drugs. They displayed different levels of antibacterial activity, with compound 7 showing essentially the highest antipseudomonal activity. As for antifungal action, the compounds under investigation, unfortunately, had no inhibitory effects against test fungi isolates except for 7 and 20, that revealed slight inhibition.

New tricyclic pyrimidinone derivatives were obtained from the corresponding thiazolopyrimidinone or hydrazino systems. The annelation of tricyclic hydrazino compound with 1,2,4-triazole and tetrazole moieties gave novel tetracyclic condensed pyrimidinones. The investigation of the antimicrobial properties of tricyclic and tetracyclic pyrimidinones, by agar-well diffusion assay, was carried out against six pathogenic bacteria (Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella spp, and Salmonella typhyrium) and four pathogenic fungi (Aspergillus flavus, Aspergillus niger, Aspergillus fumigatus, and Trichderma horozianum). Most of the compounds tested exhibited some degree of antimicrobial activity against microorganisms. Among these compounds, 4-benzylidenhydrazino-8-cyano-7-(furan-2-yl)thiazolo[3,2-a:4,5-d′]dipyrimidin-9-one (12) showed the most favorable antibacterial activity, while compound 17 showed the highest effect on fungi. Interestingly, tetrazole derivative 19 displayed a remarkable effect on fungi much more than the corresponding 3-substituted triazole derivatives on the one hand, whereas the lowest effect on bacteria on the other.

New derivatives of thieno[2,3- d ]pyrimidin-4-one, 4a-c, and 6 were respectively synthezised based on thiophene derivative, 2c, ortho -disposed amino and ester groups. Carbohydrazide, bearing 7, was obtained by hydrazinolysis of 3-ethoxycabonylmethyl derivative, 4c. Compounds 4b and 7 were used to build up two series of novel 3-substituted-methylthieno[2,3- d ]pyrimidin-4-ones, 7-11, and their corresponding 3-substituted-amino analogues 12, 15a,b, 18, which were of significant interest for biological study. The new thieno[2,3- d ]pyrimidin-4-one derivatives, with various groups in position 3, were screened for their preliminary antimicrobial activity against a representative panel of Gram-positive and Gram-negative bacteria as well as fungi strains. The compounds tested displayed different levels of antibacterial and antifungal effects, with the assays carried out on six pathogenic bacteria and six pathogenic fungi. Of these compounds, the 3-unsubstituted-thieno[2,3- d ]pyrimidin-4(3 H )-one, 4a, showed the lowest effect on pathogenic bacteria, while the corresponding 3-substituted analogues produced inhibitory effects against bacteria similar or superior to the reference drug Tetracycline. For those derivatives of thieno[2,3- d ]pyrimidin-4-one in which the 3-position contains a methylene moiety, it has been observed that the antibacterial effect was in general found to be significantly higher than the corresponding analogues with a substituted-amino moiety in position 3. Despite promising in vitro antibacterial activity of the new thienopyrimidin-4-ones, only compounds 7, 10 and 11, among the compounds tested, exhibited some kind of antifungal activity. The detailed synthesis and biological screening data were reported.

The role of beta-aminovinyl ketones as synthetic intermediates has been well categorised, but recent developments have shown an interesting array of applications and new chemotherapeutic potential, both in the preparation of biologically active heterocycles and as pharmacophores in their own right.Medicinal chemists are accustomed to using the products of Knoevenagel-type condensations as auxiliaries for the synthesis of N-containing heteroaromatic compounds. One such example of these chemical building blocks are beta-aminovinyl ketones-valuable synthetic intermediates that have been used in the preparation of pyridines, pyrimidines, pyrazoles, and many other heterocyclic motifs. This review highlights their recent use in the synthesis of biologically active targets as part of drug discovery programmes and in natural product synthesis. However, it is becoming increasingly evident that the enaminone motif may serve as a therapeutic pharmacophore in its own right. This review highlights the range of biological responses that beta-aminovinyl ketones elicit, including as antitumour, antibacterial, and anticonvulsant agents. Thus, with a broad spectrum of biological properties and as versatile chemical intermediates, it is clear that beta-aminovinyl ketones offer great potential in the search for new chemotherapeutic agents.

β-aminocrotononitrile (1) reacted with either cyanothioacetamide to give (3) or malononitrile to afford an anion (5). Pyridine-2(1H)-thione (4) was obtained by boiling of (3) in ethanol and Et 3N or treatment of (5) with H 2S, respectively. The reaction of anion 5 with isothiocyanates (6) gave N-substituted pyridine-2(1H)-thiones (7). N-Substituted pyridine-2(1H)-thiones (7) can be used for the preparation of pyrido[2,3-d]pyrimidines (8a–e) and (10a–e), or the preparation of pyrido[1,2-a]pyrimidines (12a–d). 1,8-Naphthyridine derivatives (14a–d) and (16a–e) can also be obtained from pyridine-2(1H)-thione (7). Finally, 1,8-naphthyridine derivatives (16a–e) can be used for the preparation of tetracyclic compounds 17a–c and 18a,b.

Synthesis of the new 4-hydrazinopyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines 7a,b was reported. Their reactivity toward a variety of carbon electrophiles and active methylene reagents was studied to give pyridothienotraizolopyrimidines as well as other substituted phthalazinyl- and pyrazolyl-pyridothienopyrimidine derivatives. The antimicrobial activity of some newly synthesized compounds was evaluated. © 2005 Wiley Periodicals, Inc. 16:298–307, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20126

Benzo[b]thiophen-2-yl-hydrazonoesters 4 were synthesized by coupling of 2-diazo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1) with either ethyl cyanoacetate or ethyl acetoacetate. The reactivity of 4 toward a variety of nitrogen nucleophiles was investigated to yield pyrazole, isoxazole, pyrimidine, triazine, pyrazolopyridine, and pyrazolopyrimidine derivatives. © 2003 Wiley Periodicals, Inc. 15:15–20, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/.hc10205

Ethyl α-(3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylhydrazono)acetates 1 were prepared and established as previously described by our research group. Their reactivity toward a variety of active methylene reagents was studied to give pyran, pyridine, and pyridazine derivatives. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:300–306, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20019

Several new pyrrolopyrazoles were synthesized via the reactions of each of 2-thiophenecarboxaldehyde thiazolonylhydrazone or 2-furaldehyde thiazolonylhydrazone with N -substituted maleimides followed by partial dehydogenation using bromobenzene and complete aromatization using nitrobenzene. Structures were established on the basis of elemental analyses and spectroscopic data studies.

Several new pyrrolopyrazoles were synthesised via the reaction of thiazolonylarylhydrazones with N-arylmaleimides followed by partial dehydrogenation using bromobenzene and complete aromatization using nitrobenzene. Structures were elucidated by elemental analyses and spectral data studies.

The reactivity of 4-ethoxymethylene-2-phenyloxazol-5(4H)-one and 4-dimethylamino methylene-2-phenyloxazol-5(4H)-one toward amines and active methylene reagents under microwave heating is reported. A new 3-aroylamino-4-pyridone synthesis is described.

New derivatives of thieno[3,2-d]pyrimidine and thieno[2,3-b]pyrrole 5a,b and 6a,b, respectively, were obtained from the corresponding thiophene-2-carboxamides 4a,b. On the basis of compounds 5b, 6a and 6b, two novel series of tricyclic- and tetracyclic-condensed pyrimidines 8-15 and 16-19, respectively, were synthesized by the application of the cyclization reactions of 5b and 6a,b with a variety of commercially available reactants. Geometry optimization of selected structures, using the AM1 semiemperical method, revealed a smaller ionization potential and a lower degree of conformational freedom for the tetracyclic pyrimidine derivatives relative to their tricyclic counterparts. Interestingly, computation of the solvation free energies of the lowest energy conformers at physiological conditions indicated that the series is highly soluble under these conditions. The trend in solubility as implied by the relative magnitudes of the solvation free energies is suggestive of a greater contribution of higher moments of charge distribution in modulating the interaction of the structures with the biological environment which could be detrimental for the binding modes of these structures to their putative receptor sites.

With a view to find new therapeutic agents against microbial infections, two novel series of tricyclic and monocyclic 5-(phenylazo)thiophene systems are synthesized starting from 3-amino-2-thioxopyrimidinone (III) and 2-cyanoacetamidothiophene (XII), respectively.

Various new compounds containing a thiazolopyrimidine scaffold as part of a tricyclic or tetracyclic framework are synthesized and evaluated for their antibacterial and antifungal activities.

3-Diethylaminoacrylonitrile (1) reacts with hydrazonyl halides (2a-d) to yield 1,3-disubstituted pyrazole-4-carbonitriles 5a-d. The acetyl 1-p-chlorophenylpyrazole-4-carbonitrile (5a) condensed with hydrazine hydrate to yield the bishydrazone 10 and with dimethylformamide dimethylacetal to yield 1-aryl-3-(3-dimethylamino)acryloyl pyrazole-4-carbonitrile (11). This enamine reacts with hydrazine hydrate to yield the pyrazolylpyrazole (12) and with naphthoquinone to yield the 3-naphthofuranoyl pyrazole 13. The pyra-zolyl pyridine derivative 14 was obtained upon treatment of 11 with acetylacetone in the presence of ammonium acetate. Compound 11 was coupled with p-chlorobenzene diazonium chloride to yield the hydrazone 16 that was coupled further with p-chlorobenzenediazonium chloride to yield the formazane 18.

Heterocyclic enamines1 reacted with ethyl acetoacetate to afford the corresponding amide derivatives2. Treatment of2 with carbon disulphide yielded the dipotassium salts3which reacted in-situ with a variety of α -haloketones to give the respective substituted thiophenes5,8, and13. The reactivity of the latter products towards various chemical reagents was studied to yield their fused thiophene derivatives7,10,12, and14, respectively. Some representative compounds were tested for antimicrobial activity.

3-Aminoacrylonitrile derivatives (1d–g) coupled with aromatic and heteroaromatic diazonium salts yielding arylhydrazonals and pyrazolo[5,1-c]triazines. The enaminonitriles 1d–g condensed to form dienes 6a–c on reflux in acetic acid. The latter underwent Diels-Alder type addition to naphthoquinone. Aminopyrazolopyrimidines were obtained from reaction of 1d–g with heteroaromatic aminoazoles. Enaminonitrile 1d formed pyran 21 with benzylidene malononitrile, and dihydropyrimidine 22 with benzaldehyde and urea.

The molecular structures and spectral properties of α-haloketones as well as their syntheses are analyzed and reviewed. Their reactivity towards oxygen, nitrogen, and sulfur nucleophiles, carboxylic acids, carbon nucleophiles, alkenes, and alkynes are discussed.

Ethyl α-(3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylhydrazono)acetates 1 were prepared and established as previously described by our research group. Their reactivity toward a variety of active methylene reagents was studied to give pyran, pyridine, and pyridazine derivatives. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:300–306, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20019

2-Amino-4,5,6,7-tetrahydrobenzo[b]- thiophene-3-carboxamide (1) was prepared according to Gewald procedure. Its reactivity toward a variety of chemical reagents was studied to give thienopyridines and -pyrimidines. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:459–467, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10179