Elaboration of chitosan nanoparticles loaded with star anise extract as a therapeutic system for lung cancer: Physicochemical and biological evaluation.

The research study aimed to maximize the important medical role of star anise extract (SAE) through its loading on a widely available natural polymer (chitosan, Cs). Thus, SAE loaded chitosan nanoparticles (CsNPs) was prepared. The finding illustrated the formation of spherical particles of SAE loaded CsNPs as proved by transmission electron microscope (TEM). In addition, the average particle size of CsNPs and SAE loaded CsNPs are 131.8 ± 24.63 and 318.5 ± 73.94 nm, respectively. Scanning electron microscope (SEM) showed the presence of many spherical particles deposited on the surface of CsNPs owing to the deposition of SAE on the surface and encapsulated into pores of CsNPs. It also showed the presence of elements such as sodium, potassium, copper, magnesium, zinc, calcium, and iron, as well as the elements that accompanied with CsNPs: carbon, oxygen, nitrogen, and phosphorus. The extract was rich in bioactive components, such as anethole, shikimic acid, and different flavonoids, contributing to its medicinal qualities. The bioactive molecules in SAE were assessed by chromatographic analysis. Using the agar well diffusion test, the antibacterial qualities of CsNPs and SAE loaded CsNPs were evaluated against pathogenic bacteria linked to lung illnesses. The most significant inhibition zones showed that the SAE loaded CsNPs had the most antibacterial activity. The anticancer activity using MTT assay was used in the biological assessments to determine the cytotoxicity against the NCl-H460 lung cancer cell line. The results showed that CsNPs loaded with SAE considerably decreased cell viability in a dose-dependent manner, with the most significant anticancer impact by SAE loaded CsNPs. Furthermore, in vivo tests on lung cancer therapy revealed that when compared to other treatment groups, the SAE loaded CsNPs group showed the greatest reduction in tumor biomarkers and inflammation, as seen by decreased levels of Plasma malondialdehyde (MDA), tumor protein 53 (p53), Tumor necrosis factor-alpha (TNF- alpha), and fibronectin. Results concluded that these thorough characterizations, biological assessments, and antibacterial tests have confirmed the effective integration of SAE into CsNPs. Further, SAE loaded CsNPs could be a suitable option for various biomedical applications in tackling lung cancer and the inactivation of bacterial infection.

Mechanistic Insights into Bisphenol A-Mediated Male Infertility: Potential Role of Panax Ginseng Extract.

Male infertility is identified by the inability of a man to successfully impregnate his fertile female partner, even following a year of regular unprotected sexual intercourse. About half of all infertility cases are attributed to what is known as "male factor" infertility. The escalating prevalence of male infertility in the contemporary era across the globe can be largely attributed to environmental pollution, which is the common etiological factor due to the ubiquitous presence of the environmental contaminants. Bisphenol A is recognized as an endocrine-disrupting chemical that has adverse effects on both male and female reproductive systems. On the other hand, numerous studies have demonstrated that Panax ginseng possessed the potential to improve male infertility parameters; promote spermatogenesis, recover the quality and motility of sperm and enhance testicular functions as it acted as a natural androgen supplement. The objective of this review is to offer a summary of the findings obtained from the current research data on the insult of bisphenol A (BPA) on male infertility and its supposed mode of action, as well as shed light on the potent ameliorative role of Panax ginseng extract, with a special focus on the mechanism behind its action. This review delivers a clear understanding of BPA mechanism of action on male infertility and the presumed risks deriving from its exposure. Also, this review provides evidence for the functional role of Panax ginseng extract in restoring male fertility.

Ionic Liquids Immobilized Synthesis of New Xanthenes Derivatives and their Antiproliferative, Molecular Docking, and Morphological Studies.

BACKGROUND: Xanthenes and benzoxanthenesare are highly valuable compounds in organic chemistry and medicinal chemistry. Xanthene derivatives were found to have many applications in medicinal chemistry. OBJECTIVE: This work aims to explore the synthesis of xanthene derivatives with various substituents and find the possibility of their uses as anticancer agents. METHODS: The basic starting compound through this work was the 2,3-dihydro-1H-xanthen-1-one (3), which was synthesized from the reaction of cyclohexan-1,3-dione and 2-hydroxybenzaldehyde. Compound 3 was used to synthesize new thiophene, pyrimidine, isoxazole, and thiazole derivatives based on the xanthenes nucleus. Fused xanthene derivatives were obtained through further heterocyclization reactions. Multicomponent reactions expressed in this work were carried out in the presence of solvent catalyzed by Et3N and in solvent-free ionic liquid immobilized catalyst. RESULTS: Cytotoxicity for the newly synthesized compounds toward cancer cell lines was measured, and the results revealed that many compounds exhibited high inhibitions. CONCLUSION: The antiproliferative activity of the synthesized compounds was studied on six selected cancer cell lines. The nature of the heterocyclic ring and the variations of substituted groups showed a high effect through the inhibitions of the tested compound.

Anti-proliferative, Morphological and Molecular Docking Studies of New Thiophene Derivatives and their Strategy in Ionic Liquids Immobilized Reactions.

BACKGROUND: A number of research were conducted on the pyran and thiophene derivatives, which were attributed to have a wide range of biological activities, including anti-plasmodial, as well as acting as caspase, hepatitis C and cancer inhibitors. OBJECTIVE: The multicomponent reactions of the 5-acetyl-2-amino-4-(phenylamino)-thiophene-3-carbonitrile produced biologically active target molecules like pyran and their fused derivatives. Comparison between regular catalytic multi-component reactions and solvent-free ionic liquids immobilized multicomponent was studied. METHODS: The multicomponent reactions in this work were carried out not only under the reflux conditions using triethylamine as a catalyst but also in solvent-free ionic liquids immobilized magnetic nanoparticles (MNPs) catalysts. RESULTS: Through this work, thirty-one new compounds were synthesized and characterized and were evaluated toward the six cancer cell lines, namely A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460. The most active compounds were further screened toward seventeen cancer cell lines classified according to the disease. In addition, the effect of compound 11e on the A549 cell line was selected to make further morphological changes in the cell line. The Molecular docking studies of 11e and 11f were carried and promising results were obtained. CONCLUSION: The synthesis of heterocyclic compounds derived from thiophene derivatives has been receiving significant attention. After a detailed optimizing study, it has been found that the solvent-free ionic liquids immobilized multi-component syntheses afforded a high yield of compounds, opening a greener procedure for this synthetically relevant transformation. Many of the synthesized compounds can be considered anticancer agents, enhancing further studies.

New Approaches for the Synthesis N-alkylated Benzo[b]thiophene Derivatives together with their Antiproliferative and Molecular Docking Studies.

BACKGROUND: 2-Amino thiophene derivatives are important compounds not only for their uses in many heterocyclic reactions but also due to their wide range of pharmaceutical and biological activities. OBJECTIVE: The aim of this work was to explore a number of new heterocyclic derivatives, studying their inhibitions toward cancer cell lines and studying their structure activity relation ship. METHODS: Alkylation of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was achieved through its reaction with chloroacetone and 2-bromo-1-(4-aryl)ethanone derivatives to give compounds 3 and 11a-c. The produced compoumds were subjected to further heterocylization reactions and cytotoxic evaluation against the three cancer cell lines MCF-7, NCI-H460 and SF-268, together with the normal cell line WI 38. Further evaluations were obtained through studying their inhibitions against cancer cell lines classified according to the disease. Anticancer screening against hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines for all compounds together with the molecular docking of 12c, 12d, 12e and 12f were studied. RESULTS: Anti-proliferative evaluations and inhibitions for all of the synthesized compounds showed that many compounds exhibited high inhibitions. CONCLUSION: Toward the three cancer cell lines, compounds 3, 5a, 7a, 9a, 9b, 11b, 12b, 12d, 12e, 12f, 14c, 14e, 14f, 15e, 15f, 16e, 16f, 17c, 18b, 22a and 22c were the most cytotoxic compounds. The high activities of some compounds were attributed to the presence of the electronegative CN and or Cl groups within the molecule. Most of the tested compounds exhibited inhibitions higher than the reference doxorubicin toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines. The score of binding energy of compounds 12c, 12d, 12e and 12f was close to the reference Foretinib which appeared through the molecular docking results of such compounds.

Synthesis, Molecular Docking, c-Met Inhibitions of 2,2,2-Trichloroethylidene- cyclohexane-1, 3-dione Derivatives Together with their Application as Target SARS-CoV-2 main Protease (Mpro) and as Potential anti-COVID-19.

BACKGROUND: The lack of anti-COVID-19 treatment to date warrants urgent research into potential therapeutic targets. Virtual drug screening techniques enable the identification of novel compounds that target the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Main Protease (Mpro). OBJECTIVE: The binding of the halogenated compounds to Mpro may inhibit the replication and transcription of SARS-CoV-2 and, ultimately, stop the viral life cycle. In times of dire need for anti- COVID-19 treatment, this study lays the groundwork for further experimental research to investigate these compounds' efficacy and potential medical uses to treat COVID-19. METHODS: New heterocyclic compounds were synthesized through the first reaction of cyclohexane- 1, 3-dione (1a) or dimedone (1b) with trichloroacetonitrile (2) to give the 2,2,2-trichloroethylidene) cyclohexane-1,3-dione derivatives 3a and 3b, respectively. The latter compounds underwent a series of heterocyclization reactions to produce biologically active compounds. RESULTS: Novel compounds, including fused thiophene, pyrimidine and pyran derivatives, were synthesized and tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and Vaccinia D1-D12 complex to evaluate their specificity and their molecular modeling was also studied in the aim of producing anti-COVID-19 target molecules. CONCLUSION: The results showed that compounds 10a, 10b, 10c, 10e, 10f, 10g and 10h showed high % inhibitions against SARs-Covnsp 14. Whereas compounds 5a, 7a, 8b, 10a, 10b, 10c and 10i showed high inhibitions against hRNMT. This study explored the binding affinity of twenty-two halogenated compounds to the SARS-CoV-2 MPro and discovered fifteen compounds with higher binding affinity than Nelfinavir, of which three showed remarkable results. c-Met kinase inhibitions of 10a, 10f, 10g and 10h showed that all compounds exhibited higher inhibitions than the reference Foretinib.

Anti-proliferative, c-Met Inhibitions, and PAINS Evaluations of New Thiophene, Thiazole, Coumarin, Pyran, and Pyridine Derivatives.

BACKGROUND: 1,3-Diones are versatile reagents used for many heterocyclic transformations. Among such groups of compounds, cyclohexane-1,3-dione is widely used in organic synthesis to produce biologically active compounds. OBJECTIVE: In this work, target molecules were synthesized from tetrahydrobenzo[b]thiophen-3- carboxamide derivative with different substituents, and their structure-activity relationships were discussed in detail. METHODS: Cyclohexane-1,3-dione underwent different multi-component reactions to produce fused thiophene, thiazole, coumarin, pyran, and pyridine derivatives. The anti-proliferative activity of the newly synthesized compounds toward the six cancer cell lines, namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions of the most active compounds toward cancer cell lines classified according to the disease were also studied. Furthermore, Pan Assay Interference compounds (PAINS) of the selected compounds were analyzed, along with the c- Met inhibitions. RESULTS: Anti-proliferative evaluations were performed for all of the synthesized compounds, in which the varieties of substituents through the aryl ring and the heterocyclic ring afforded compounds with high activities. Inhibition activity against the cancer cell lines classified according to the disease, c-Met, and PAINS of the synthesized compounds were measured. CONCLUSION: Compounds 3, 13a, 13b, 14a, 16f, 17a, 28, 30a, and 31were the most cytotoxic compounds toward the six cancer cell lines. Inhibition toward cancer cell lines classified according to the disease showed that, in most cases, the presence of the electronegative CN and or Cl groups within the molecule was responsible for its high activity.

New Approaches for the Synthesis of 2,3,5,6-Tetrahydrobenzo[d]thiazole Derivatives and their Anti-Proliferative, c-Met Enzymatic Activity and Tyrosine Kinases Inhibitions.

BACKGROUND: Due to their biological applications, many tetrahydrobenzo[d]thiazole derivatives were considered the most important class of heterocyclic compounds. There are many drugs known in the market containing the thiazole moiety responsible for the high drug activity. OBJECTIVE: This work aimed to produce novel heterocyclic compounds such as pyrazole, isoxazole, thiophene, chromeno[ 7,8-d]thiazole, and thiazolo[4,5-h]quinoline derivatives. The newly synthesized heterocyclic compounds were evaluated against anticancer cell lines followed by c-Met enzymatic activity and tyrosine kinases inhibition for the most active compounds. METHODS: In this work, the 3-phenyl-2-thioxo-2,3,5,6-tetrahydrobenzo[d]thiazol-7(4H)-one (3) was synthesized through the reaction of cyclohexane-1,3-dione with phenyl isothiocyanate and elemental sulfur. Compound 3 showed interesting activity toward some chemical reagents producing new heterocyclic compounds that can not be obtained another way. The newly synthesized compounds were evaluated towards the six cancer cell lines. The most active compounds were selected and tested toward the c-Met enzyme by taking foretinib as the positive control. Also, the inhibitions toward the PC-3 cell line using the reference SGI-1776 were measured. Finally, the inhibitions towards the five tyrosine kinases were also tested. RESULTS: The synthesized quinoline and chromene derivatives were evaluated toward the c-Met enzyme using foretinib as the positive control. The obtained results showed that twelve compounds exhibited IC50 values less than 1.30 nM. On the other hand, sixteen compounds showed higher inhibitions than the reference SGI-1776 (IC50 4.86 nM) toward the PC-3 cell line. CONCLUSION: Novel, heterocyclic compounds were synthesized with a high impact on biological activities. All synthesized compounds were screened for their anti-proliferative effect, and most of them revealed high potent effects. In addition, the c-Met and prostate cancer cell line PC-3 inhibitions for the most active compounds showed that these compounds exhibited high inhibitions. Anti-proliferative activity of selected compounds toward cancer cell lines classified according to the disease showed that most compounds exhibited high inhibitions.

Molecular Mechanisms Underlying the Anti-Breast Cancer Stem Cell Activity of Pterocladia capillacea and Corallina officinalis Polysaccharides.

OBJECTIVE: This study aimed to appraise the activity of Pterocladia capillacea and Corallina officinalis polysaccharides against Breast Cancer Stem Cells (BCSCs). P. capillacea and C. officinalis polysaccharides were characterized to be sulfated polysaccharide-protein complexes. METHODS: Cytotoxicity of the polysaccharides against MDA-MB-231 and MCF-7 cell lines along with their impact on CD44+/CD24- and aldehyde dehydrogenase 1(ALDH1) positive BCSC population were determined. Their effect on gene expression of CSC markers, Wnt/ß-catenin and Notch signaling pathways was evaluated. RESULTS: P. capillacea and C. officinalis polysaccharides inhibited the growth of breast cancer cells and reduced BCSC subpopulation. P. capillacea polysaccharides significantly down-regulated OCT4, SOX2, ALDH1A3 and vimentin in MDA-MB-231 as well as in MCF-7 cells except for vimentin that was up-regulated in MCF-7 cells. C. officinalis polysaccharides exhibited similar effects except for OCT4 that was up-regulated in MDA-MB-231 cells. Significant suppression of Cyclin D1 gene expression was noted in MDA-MB-231 and MCF-7 cells treated with P. capillacea or C. officinalis polysaccharides. ß-catenin and c-Myc genes were significantly down-regulated in MDA-MB-231 cells treated with C. officinalis and P. capillacea polysaccharides, respectively, while being up-regulated in MCF-7 cells treated with either of them. Additionally, P. capillacea and C. officinalis polysaccharides significantly down-regulated Hes1 gene in MCF-7 cells despite increasing Notch1 gene expression level. However, significant down-regulation of Notch1 gene was observed in MDA-MB-231 cells treated with P. capillacea polysaccharides. CONCLUSION: Collectively, this study provides evidence for the effectiveness of P. capillacea and C. officinalis polysaccharides in targeting BCSCs through interfering with substantial signaling pathways contributing to their functionality.

Synthesis and Anticancer Evaluations of Novel Thiazole Derivatives Derived from 4-Phenylthiazol-2-amine.

Many novel thiazole derivatives were designed and synthesized using 4-phenylthiazol-2-amine. The reactivity of the latter compound toward different chemical reagents was studied. The structure of the newly synthesized compounds was established based on elemental analysis and spectral data. Furthermore, twenty compounds of the synthesized systems were selected and evaluated in (µM) as significant anticancer agents towards three human cancer cell lines [MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and SF-268 (CNS cancer)] and normal fibroblasts human cell line (WI-38). The results showed that compounds 9 and 14a displayed higher effeciency than the reference doxorubicin.

Multi-Component Reactions of Cyclohexan-1,3-dione: Synthesis of Fused Pyran, Pyridine, Thiophene and Pyrazole Derivatives with c-Met, Anti-Proliferative Activities.

BACKGROUND: Recently, products of Multi-Component Reactions (MCR's) acquired special attention due to their wide range of pharmacological activities especially therapeutic activities. In the market it was found that many pharmacological drugs containing the pyran and pyridine nucleus that were produced through MCR's were found. OBJECTIVE: This work aims to synthesize target molecules not only possess anti-tumour activities but also c-Met and prostate cancer inhibitors. The target molecules were obtained starting from cyclohexan-1,3-dione through its multi-component reactions to produce anticancer target molecules. METHODS: Cyclohexane-1,3-dione underwent different multi-component reactions to produce fused pyran, pyridine and thiophene derivatives. The anti-proliferative activity of the newly synthesized compounds among the synthesized compounds toward the six cancer cell lines, namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions toward c-Met kinase and prostate cancer cell line were studied. Antitumor evaluations toward seventeen cancer cell lines subpanel, for certain compounds, were also demonstrated according to the diseases. Pim-1 kinase inhibitions of the most active compounds were also measured. RESULTS: Anti-proliferative evaluations, c-Met and Pim-1 kinase inhibitions were performed for most of the synthesized compounds where the varieties of substituent through the aryl ring and the heterocyclic ring afforded compounds with high activities. CONCLUSION: Compounds 4b, 6b, 8b, 9a, 11b, 12b, 17b, 18b, 19, 22c, 23b, 25b and 26b were the most cytotoxic compounds toward the six cancer cell lines. Inhibitions toward c-Met kinase and prostate cancer cells showed that the presence of the electronegative Cl group within the molecule were responsible for its high activity. In addition, inhibitions toward Pim-1 kinase exhibited that most of tested compounds showed high inhibitions.

The Uses of Dimedone for the Synthesis of Thiophene, Thiazole and Annulated Derivatives with Antitumor, Pim-1 Kinase Inhibitions, PAINS Evaluations and Molecular Docking.

BACKGROUND: Dimedone is considered as one of the most important classes of compounds belonging to cyclohexan-1,3-dione. Such groups of compounds were considered as precursors for many pharmaceutically active heterocyclic compounds. OBJECTIVE: The target molecules in this work were synthesized from arylhydrazones of dimedone with different substituents enhancing the study of their structure-activity relationship. METHODS: Arylhydrazones of dimedones were subjected to a series of heterocyclization reactions affording annulated compounds. The anti-proliferative activities of the synthesized molecules were evaluated against six cancer cell lines. In addition, inhibitions toward tyrosine kinases, Pim-1 kinases and PAINS of the most active compounds were also studied. c-Met enzymatic inhibitions and molecular docking studies were carried out for three compounds. RESULTS: Anti-cancer evaluations together with tyrosine and Pim-1 kinases of most of the synthesized compounds were carried out through this work. The study revealed that changing of substituents had a strong impact on the activity of the molecule. CONCLUSION: Many of the synthesized compounds exhibited high inhibitions towards the six cancer cell lines. This will encourage further work through the synthesis of target molecules with the same ring systems. The three compounds 7b, 8c and 12b that revealed excellent inhibitions were tested against c-Met kinase and their molecular modelling was expressed.

New Approaches for the Synthesis of Heterocyclic Compounds Corporating Benzo[d]imidazole as Anticancer Agents, Tyrosine, Pim-1 Kinases Inhibitions and their PAINS Evaluations.

BACKGROUND: Benzo[d]imidazoles are highly biologically active, in addition, they are considered as a class of heterocyclic compounds with many pharmaceutical applications. OBJECTIVE: We are aiming in this work to synthesize target molecules that possess not only anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the benzo[d]imidazole derivatives followed by their heterocyclization reactions to produce anticancer target molecules. METHODS: The 1-(1H-benzo[d]imidazol-2-yl)propan-2-one (3) and the ethyl 2-(1H-benzo[d]imidazol-2- yl)acetate (16) were used as the key starting material which reacted with salicylaldehyde to give the corresponding benzo[4,5]imidazo[1,2-a]quinoline derivatives. On the other hand, both of them were reacted with different reagents to give thiophene, pyran and benzo[4,5]imidazo[1,2-c]pyrimidine derivatives. The synthesized compounds were evaluated against the six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460 together with inhibitions toward tyrosine kinases, c-Met kinase and prostate cancer cell line PC-3 using the standard MTT assay in vitro, with foretinib as the positive control. RESULTS: Most of the synthesized compounds exhibited high inhibitions toward the tested cancer cell lines. In addition, tyrosine and Pim-1 kinases inhibitions were performed for the most active compounds where the variation of substituent through the aryl ring and heterocyclic ring afforded compounds with high activities. Our analysis showed that there is a strong correlation between the structure of the compound and the substituents of target molecules. CONCLUSION: Our present research proved that the synthesized heterocyclic compounds with varieties of substituents have a strong impact on the activity of compounds. The evaluations through different cell lines and tyrosine kinases indicated that the compounds were the excellent candidates as anticancer agents. This could encourage doing further research within this field for the building of compounds with high inhibitions.

Synthesis and Anti-Proliferative Evaluations of New Heterocyclic Derivatives Using 5,6,8,9-Tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one Derivatives Derived from Cyclohexa-1,4-dione.

BACKGROUND: Recentlty, pyrazoloquinazoline derivatives acquired a special attention due to their wide range of pharmacological activities, especially therapeutic. Through the market, it was found that many pharmacological drugs containing the quinazoline nucleus were known. OBJECTIVE: The aim of this work is to synthesize target molecules possessing not only anti-tumor activities but also kinase inhibitors. The target molecules were obtained through the synthesis of a series of 5,6,8,9- tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives 4a-i using the multi-component reactions of cyclohexane- 1,4-dione (1), the 5-amino-4-(2-arylhydrazono)-4H-pyrazol-3-ol derivatives 2a-c, the aromatic aldehydes 3a-c, respectively. The synthesized compounds were evaluated against c-Met kinase, PC-3 cell line, and different kinds of cancer cell lines together with normal cell line, tyrosine kinases, and Pim-1 kinase. METHODS: Multi-component reactions were adopted using compound 1 to get different 5,6,8,9- tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives which underwent further heterocyclization reactions. The c-Met kinase activity of all compounds was evaluated using Homogeneous Time-Resolved Fluorescence (HTRF) assay, taking foretinib as the positive control. The anti-proliferative activity of all target compounds against the human prostatic cancer PC-3 cell line was measured using MTT assay using SGI-1776 as the reference drug. All the synthesized compounds were assessed for inhibitory activities against A549 (non-small cell lung cancer), H460 (human lung cancer), HT-29 (human colon cancer), and MKN-45 (human gastric cancer) cancer cell lines together with foretinib as the positive control by an MTT assay. RESULTS: Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed for the synthesized compounds, where the varieties of substituents through the aryl ring and the thiophene moiety afforded compounds with high activities. CONCLUSION: The compounds with high antiproliferative activity were tested towards c-Met and the results showed that compounds 4e, 4f, 4g, 4i, 6i, 6k, 6l, 8f, 8i, 10d, 10e, 10f, 10h, 12e, 12f, 12g, 12h, 12i, 14f, 14g, 14h, and 14i were the most potent compounds. A further selection of compounds for the Pim-1 kinase inhibition activity showed that compounds 4f, 6i, 6l, 8h, 8i, 8g, 10d, 12i, and 14f were the most active compounds to inhibit Pim-1.

New Approaches for the Synthesis of Fused Thiophene, Pyrazole, Pyran and Pyridine Derivatives with Anti-Proliferative Together with c-Met Kinase and Prostate Cancer Cell Inhibitions.

BACKGROUND: Recently multi-component reactions producing pyran and pyridine derivatives acquired a special attention due to their wide range of pharmacological activities, especially therapeutic activities. Through the market, it was found that many pharmacological drugs containing the pyran and pyridine nucleus were known. OBJECTIVE: We are aiming in this work to synthesize target molecules possess not only anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from cyclohexane-1,3-dione followed by its heterocyclization reactions to produce anticancer target molecules. METHODS: This work demonstrated multi-component reactions of cyclohexan-1,3-dione with aromatic aldehydes and diethylmalonate using triethylamine as a catalyst to give the 7,8-dihydro-4H-chromen-5(6H)-one derivatives 4a-c. The reaction of compounds 4a-c with either of hydrazine hydrate of phenylhydrazine gave the chromeno[2,3-c]pyrazole derivatives 5a-f, respectively. In addition, further heterocyclization reactions were adopted to give the chromeno[3,2-d]isoxazole, chromene-3-carboxamide derivatives. Moreover, the multicomponent reaction of cyclohexan-1,3-dione (1) with either of aromatic aldehydes and diethylmalonate using a catalytic amount of ammonium acetate gave the 1,4,5,6,7,8-hexahydroquinoline derivatives 13a-c. The antiproliferative activities of the synthesized compounds toward the six cancer cell lines namely A549, H460, HT- 29, MKN-45, U87MG, and SMMC-7721 were studied. In addition, the c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured. RESULTS: Anti-proliferative evaluations, c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured, and the results obtained in most cases indicated that the presence of electronegative Cl group through the molecule favour the inhibitions. CONCLUSION: The compounds with high anti-proliferative activity towards the cancer cell lines were 4a, 4b, 6d, 6e, 6f, 10e, 10f, 12c, 14e, 14f, 15c, 16d, 16e, 16f, 19c and 20c. Compounds 4b, 6c, 6d, 8b, 10c, 10d, 12b, 13b, 14c, 14d, 15b, 16c, 16d, 17b, 17c, 19b, 20b and 20c exhibited high potency against c-Met kinase and compounds 4a, 4b, 6b, 6c, 6d, 6f, 8b, 8c, 10c, 10d, 10e, 12b, 12c, 13a, 13b, 13c, 14c, 14d, 14e, 14f, 15b, 15c, 16b, 16c, 16d, 17b, 17c, 19c, 19d, 20a, 20b and 20c displayed high inhibitions toward PC-3 cell line.

Heterocyclization of 2-(2-phenylhydrazono)cyclohexane-1,3-dione to Synthesis Thiophene, Pyrazole and 1,2,4-triazine Derivatives with Anti-Tumor and Tyrosine Kinase Inhibitions.

BACKGROUND: Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the thiazole nucleus were known. OBJECTIVE: This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed by their heterocyclization reactions to produce anticancer target molecules. METHODS: The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene, thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. RESULTS: Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities. CONCLUSION: The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds 3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero PAINS alert and can be used as lead compounds.

Synthesis of Heterocyclic Compounds Derived From Dimedone and their Anti-tumor and Tyrosine Kinase Inhibitions.

The reaction of dimedone with arylaldehydes gave the benzylidene derivatives 3a-c, the latter underwent a series of heterocyclization reactions to give fused thiophene, pyrazole isoxazole and pyridazine derivatives. The synthesized compounds were evaluated against different kinds of cancer cell lines together tyrosine kinases and Pim-1 kinase inhibitions. All the synthesized compounds were assessed for the inhibitory activities against A549 (non-small cell lung cancer), H460 (human lung cancer), HT-29 (human colon cancer) and MKN-45 (human gastric cancer) cancer cell lines together with foretinib as the positive control by a MTT assay. The promising compounds were 3c, 5b, 5e, 5f, 7c, 7f, 9c, 11b, 12c, 12d, 13b, 13d, 14b, 16c and 16d among the tested compounds. On the other hand, compounds 5b, 5e, 5f, 7c, 11b, 12c, 12d, 13d, 14b, 16c and 16d were the most effective inhibitors against tyrosine kinases and compounds 5b, 11b, 12d, 13d, 14b and 16c were the most potent against Pim-1 kinase.

Heterocyclization of 2-Arylidenecyclohexan-1,3-dione: Synthesis of Thiophene, Thiazole, and Isoxazole Derivatives with Potential Antitumor Activities.

BACKGROUND: Thiophene, thiazole, and isoxazole derivatives are present in a wide range of natural and synthetic compounds with heterogeneous pharmacological activity. Due to their structural diversity, they are some of the most versatile classes of compounds for anticancer drug design and discovery. OBJECTIVE: Thiophene, thiazole, and isoxazole derivatives were herein designed with a dual purpose: as antiproliferative agents and kinase inhibitors. METHODS: The test compounds were synthesized in moderate to high yields through a simple methodology. Tetrahydrobenzo[b]thiophen-5-one derivatives 5a-f were prepared from the reaction of 2-arylidencyclohexan- 1,3-dione 3a-c with elemental sulfur and either of malononitrile (4a) or ethyl cyanoacetate (4b) in 1,4-dioxan in the presence of triethylamine. Compounds 5a,b were used for the synthesis of thiophene, thiazole, and isoxazole derivatives through their reactions with different chemical reagents. RESULTS: Antiproliferative evaluations, c-Met kinase, and Pim-1 kinase inhibitions were performed where some compounds revealed high activities. In all cases, antiproliferative activity and the kinase inhibitions were performed against six cancer cell lines and five tyrosine kinases, respectively. Where the most cytotoxic compounds were 3c, 5d, and 16c with IC50's 0.29, 0.68, and 0.42µM, respectively, against the A549 cell line. CONCLUSION: The anti-proliferative activities of the newly synthesized compounds were evaluated against the six cancer cell lines (A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460). The most potent compounds toward the cancer cell lines (3a, 3c, 5d, 7c, 11c, 16a, and 16c) were further investigated towards the five tyrosine kinases (c-kit, FIT-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5d, and 16c were selected for testing of their inhibition for the Pim-1 kinase due to their anti-proliferation activities against the cancer cell lines and their high activities against the tyrosine kinases.

Synthesis and Biological Evaluation of Novel 4,5,6,7-Tetrahydrobenzo[D]-Thiazol-2- Yl Derivatives Derived from Dimedone with Anti-Tumor, C-Met, Tyrosine Kinase and Pim-1 Inhibitions.

BACKGROUND: Dimedone and thiazole moieties are privileged scaffolds (acting as primary pharmacophores) in many compounds that are useful to treat several diseases, mainly tropical infectious diseases. Thiazole derivatives are a very important class of compounds due to their wide range of pharmaceutical and therapeutic activities. On the other hand, dimedone is used to synthesize many therapeutically active compounds. Therefore, the combination of both moieties through a single molecule to produce heterocyclic compounds will produce excellent anticancer agents. OBJECTIVE: The present work reports the synthesis of 47 new substances belonging to two classes of compounds: Dimedone and thiazoles, with the purpose of developing new drugs that present high specificity for tumor cells and low toxicity to the organism. To achieve this goal, our strategy was to synthesize a series of 4,5,6,7-tetrahydrobenzo[d]-thiazol-2-yl derivatives using the reaction of the 2-bromodimedone with cyanothioacetamide. METHODS: The reaction of 2-bromodimedone with cyanothioacetamide gave the 4,5,6,7-tetrahydrobenzo[d]- thiazol-2-yl derivative 4. The reactivity of compound 4 towards some chemical reagents was observed to produce different heterocyclic derivatives. RESULTS: A cytotoxic screening was performed to evaluate the performance of the new derivatives in six tumor cell lines. Thirteen compounds were shown to be promising toward the tumor cell lines which were further evaluated toward five tyrosine kinases. CONCLUSION: The results of antitumor screening showed that many of the tested compounds were of high inhibition towards the tested cell lines. Compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 21b, 21c, 20d and 21d were the most potent compounds toward c-Met kinase and PC-3 cell line. The most promising compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 20c, 20d, 21b, 21c and 21d were further investigated against tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 6c, 11b, 11d, 14b, 15c, and 20d were selected to examine their Pim-1 kinase inhibition activity the results revealed that compounds 11b, 11d and 15c had high activities.

Synthesis of Tetrahydrobenzo[b]thiophene-3-carbohydrazide Derivatives as Potential Anti-cancer Agents and Pim-1 Kinase Inhibitors.

BACKGROUND: Tetrahydrobenzo[b]thiophene derivatives are well known to be biologically active compounds and many of them occupy a wide range of anticancer agent drugs. OBJECTIVE: One of the main aim of this work was to synthesize target molecules not only possessing anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of 4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbohydrazide derivatives using cyclohexan-1,4-dione and cyanoacetylhydrazine to give the 2-amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbohydrazide (3) as the key starting material for many heterocyclization reactions. METHODS: Compound 3 was reacted with some aryldiazonium salts and the products were cyclised when reacted with either malononitrile or ethyl cyanoacetate. Thiazole derivatives were also obtained through the reaction of compound 3 with phenylisothiocyanate followed by heterocyclization with α-halocarbonyl derivatives. Pyrazole, triazole and pyran derivatives were also obtained. RESULTS: The compounds obtained in this work were evaluated for their in-vitro cytotoxic activity against c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The results of anti-proliferative evaluations and c-Met kinase, Pim-1 kinse inhibitions revealed that some compounds showed high activities. CONCLUSION: The most promising compounds 5b, 5c, 7c, 7d, 11b, 14a, 16b, 18b, 19, 21a, 23c, 23d and 23i against c-Met kinase were further investigated against the five tyrosin kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 5b, 5c, 7d, 7e, 11b, 11c, 16c, 16d, 18c, 19, 23e, 23k and 23m were selected to examine their Pim-1 kinase inhibitions activity where compounds 7d, 7e, 11b, 11c, 16d, 18c and 23e showed high activities. All of the synthesized compounds have no impaired effect toward the VERO normal cell line.