Design and synthesis of novel hexahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as potential anticancer agents with antiangiogenic activity via VEGFR-2 inhibition, and down-regulation of PI3K/AKT/mTOR signaling pathway.

New thieno[2,3-d]pyrimidine derivatives were designed and synthesized. The National Cancer Institute (NCI) evaluated the synthesized novel compounds against a panel of 60 tumor cell lines for their antiproliferative activity. Compounds 6b, 6f, and 6g showed potent anticancer activity at 10 µM dose, with mean GI of 20.86%, 76.41%, and 31.49%, respectively. Compound 6f was selected for five-dose concentrations evaluation. Compound 6f scored a submicromolar range of GI50 values against 10 cancer cell lines, indicating broad-spectrum and potent antiproliferative activity. Compound 6f TGI values were recorded in the cytostatic range of 4.02-95.1 µM. In comparison to sorafenib, the tested compounds 6b, 6f, and 6g inhibited VEGFR-2 with IC50 values of 0.290 ± 0.032, 0.066 ± 0.004, and 0.16 ± 0.006 µM, correspondingly. Compound 6f significantly reduced the total VEGFR-2 expression and its phosphorylation. Additionally, 6f reduced the phosphorylation of PI3K, Akt, and mTOR pathway proteins. Moreover, the migratory potential of HUVECs was significantly reduced, after 72 h of treatment with compound 6f, resulting in disrupted wound healing patterns which verified the angiogenesis suppression properties of compound 6f. Compound 6f increased the total apoptosis percentage by 21.27-fold compared to sorafenib, which caused a 24.11-fold increase in the total apoptosis percentage. This apoptotic activity was accompanied by a 7.81-fold increase in the level of apoptotic caspase-3. Furthermore, the cell cycle analysis revealed that the target derivative 6f reduced cellular proliferation and induced an arrest in HCT-15 colon cancer cell cycle at the S phase. Molecular modeling was used to determine the binding profile and affinity of derivative 6f toward the VEGFR-2 active site.

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.

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.

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.

The Knoevenagel reaction of cyanoacetylhydrazine with pregnenolone: Synthesis of thiophene, thieno[2,3-d]pyrimidine, 1,2,4-triazole, pyran and pyridine derivatives with anti-inflammatory and anti-ulcer activities.

The reaction of pregnenolone with cyanoacetylhydrazine and ammonium acetate at 120°C gave the Knoevenagel condensation product 3. The latter reacted with different reagents to give thiophene, thieno[2,3-d]pyrimidine, 1,2,4-triazole and pyran derivatives. The anti-inflammatory and anti-ulcer evaluations of the newly synthesized products were evaluated and the results showed that compounds 4, 8c, 10, 11, 13c, 15a, 15c, 17a, 17b, 17e, 18a and 18f possessed higher activity compared to the rest of the compounds. In addition to this, the toxicity of these active compounds was studied against shrimp larvae where compounds 15a, 15c and 18a showed non-toxicity against the tested organisms.

Heterocyclizations of pregnenolone: novel synthesis of thiosemicarbazone, thiophene, thiazole, thieno[2,3-b]pyridine derivatives and their cytotoxicity evaluations.

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring D modification of 1 through its reaction with 4-phenyl-3-thiosemicarbazide gave the thiosemicarbazone derivative 3. The latter compound underwent heterocyclization reactions to give the thiazolyl hydrazonoandrostane and pyrazolyl semicarbazidoandrostane derivatives 5a-d, and 9a-d, respectively. On the other hand compound 1 reacted with either malononitrile or ethyl cyanoacetate to give the Knoevenagel condensated products 11a and 11b, respectively. Compounds 11a,b afforded the thiophenyl pregnane derivatives 12a and 12b, respectively, their reactivity toward some chemical reagents was studied. The cytotoxicity of the newly synthesized heterocyclic steroids against three human tumor cell lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were studied. Some of tested compounds were found to exhibit much higher inhibitory effects toward the three tumor cell lines than the reference drug, doxorubicin.

Screening for antidepressant, sedative and analgesic activities of novel fused thiophene derivatives.

This study was aimed at the synthesis of fused benzothiophene derivatives containing heterocyclic moiety. The reaction of the tetrahydrobenzo[b]thiophene derivatives 1a,b with ethoxycarbonylisothiocyanate afforded the thiourea derivatives 2a,b. Cyclization of the latter products gave the annulated benzo[b]thienopyrimidine derivatives 3a,b. Compounds 2a,b and 3a underwent a series of heterocyclization reactions through the reaction with some chemical reagents to give the new benzo[b]thienopyrimidine derivatives 5a,b to 8a-c. Also, this work was extended to study the potential role of the novel synthesized thiourea derivative 2a and benzo[b]thienopyrimidine derivatives 3a, 5b, 6a and 8b as antidepressant, sedative or analgesic agents at two doses (15 or 30 mg kg(-1) body mass). Some compounds (2a, 3a and 5b) showed mild antidepressant activity in the forced-swimming test. No compound showed sedative effect. Visceral pain evoked by i.p. injection of acetic acid in mice was significantly inhibited by all compounds at a high doses.

Novel synthesis of 1,3,4-thiadiazine derivatives and their cycloaddition reactions.

4-Phenyl-3-thiosemicarbazide 1 reacted with the alpha-halocarbonyl compounds 2a, b to give the thiosemicarbazone derivatives 3a, b. The latter compounds underwent cyclization to the 1,3,4-thiadiazine derivatives 4a, b which underwent [2 + 4] cycloaddition reactions to give the 4H-thiopyran derivatives 7a, b. The chemistry of these thiopyrans was studied. Some of the fused derivatives among them compounds 20a, 20b, 21a, 21b allowed good mycelial growth and sporulation by the two fungi. This indicates that the two fungi can use the N-containing heterocyclic ring as a nitrogen source.

Synthesis and antimicrobial evaluation of some novel cholestane heterocyclic derivatives.

This study was performed to investigate the reactivity of 5alpha-cholestan-3-one (1) towards various chemical reagents to produce new steroidal heterocyclic derivatives. The aminothieno[2, 3:2, 3]cholestane derivative 2 was synthesized according to Gewald's conditions. The diazonium salt of compound 2 coupled with malononitrile to afford dicyanomethylenhydrazinothieno[2', 3':2, 3]cholestane derivative 5. The behavior of compound 5 towards nitrogen nucleophiles and several active methylene reagents was investigated. Additionally, a variety of steroidal heterocyclic derivatives like compounds 15a, b-22a, b were synthesized starting with 5alpha-cholestan-3-one (1). The structures of the compounds were established based on the analytical and spectral data. The in vitro antimicrobial activity of some newly synthesized compounds against bacteria and fungi was studied.