Tamer Nasr

Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives

Drug resistance is a major impediment for cancer treatment, to overcome it we designed and synthesized sixteen coumarins bearing hydrazide-hydrazone moiety and evaluated them against human drug-resistant pancreatic carcinoma (Panc-1) cells and drug-sensitive (hepatic carcinoma; Hep-G2 and leukemia; CCRF) cell lines in vitro. The 6-brominated coumarin hydrazide-hydrazone derivatives (BCHHD) 7c, 8c and 10c were more potent than doxorubicin (DOX) against resistant Panc-1 cells. BCHHD 7c showed significant cytotoxicity against all tested cells (IC50: 3.60-6.50 μM) on comparison with all other coumarin hydrazide-hydrazone derivatives (CHHD), whereas BCHHDs 8c and 10c showed significant antiproliferative activity only against resistant Panc-1 cells with IC50 of 2.02 μM and 2.15 μM, respectively. All the investigated BCHHDs were able to activate caspases 3/7 and they could induce apoptosis in resistant Panc-1 cells. Microarray analysis showed that BCHHD 7c induced the expression of apoptotic- and cell cycle arrest (G2/M)- genes in resistant Panc-1 cells. Moreover, BCHHD 7c induced the up-regulation of CDKN1A, DDIT4, GDF-15 and down-regulation of CDC2, CDC20, CDK2 genes. Based on our results, we conclude that 7c could be a potent anticancer drug to overcome drug resistance in cancer and it could be highly beneficial for patients in the clinic.

Design, synthesis, antimicrobial evaluation and molecular docking studies of some new thiophene, pyrazole and pyridone derivatives bearing sulfisoxazole moiety

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. In this context, new functionalized thiophene, acrylamide, arylhydrazone, pyrazole and pyridone derivatives bearing sulfisoxazole moiety were designed, synthesized and evaluated for their in vitro antibacterial and antifungal activities. Among the synthesized compounds, thiophene 4d and 6-thioglucosylpyridone 17 displayed significant antibacterial activities against Escherichia coli (MIC, 0.007 μg/mL vs gentamycin 1.95 μg/mL) and Bacillis subtilis (MIC, 0.007 μg/mL vs ampicillin 0.24 μg/mL), respectively. Whereas, the pyrazole 6 showed the highest antifungal activity against Aspergillus fumigates (MIC, 0.03 μg/mL vs amphotericin B 0.12 μg/mL). In general, most of the synthesized compounds exhibited better antimicrobial activities than sulfisoxazole; this might be attributed to the synergistic effect of the sulfonamide and attached heterocyclic moieties as well as the increased lipophilic characters of the synthesized compounds. Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of microbial DHPS enzyme. The results provide important information for the future design of more potent antimicrobial agents.

First Synthesis of Thiophene Thioglycosides

A new method for the preparation of a new class of thiophene thioglycosides via one-pot reaction of the sodium thiophenethiolate salts with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galacto-pyranosyl bromides has been studied. The sodium thiophenethiolate salts are prepared using cyano-di-thioic analogs and their corresponding mono- and dithiolate salts.

New Trends in Synthesis of Pyrazole Nucleosides as New Antimetabolites

Pyrazole nucleosides and condensed pyrazole nucleosides exhibit various biological activities. This article describes recent synthetic approaches to their preparation, chemical properties, biological activities, and structure-activity relationships, with emphasis to selected drugs or drug candidates. Two pyrazole C-nucleoside compounds pyrazofurin (pyrazomycin) and its α-epimer pyrazofurin B are active components of potent antivirals approved for therapeutic use in human medicine aimed against various diseases caused by DNA viruses.

First Synthesis of Thienopyrazole Thioglycosides

Reported is the first method to prepare a new class of thienopyrazole thioglycosides via a one‐pot reaction of the sodium thienopyrazolthiolate salts with 2,3,4,6‐tetra‐O‐acetyl‐α‐D‐gluco‐and galactopyranosyl bromides. The sodium thienopyrazolthiolate salts are prepared using pyrazoldithioic acids and their corresponding mono ‐ and dithiolate salts.

Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran–pyrazole derivatives as anticancer agents

This study deals with design and synthesis of novel benzofuran-pyrazole hybrids as anticancer agents. Eight compounds were chosen by National Cancer Institute (NCI), USA to evaluate their in vitro antiproliferative activity at 10(-5)M in full NCI 60 cell panel. The preliminary screening of the tested compounds showed promising broad-spectrum anticancer activity. Compound 4c was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Leukemia CCRF-CEM, MOLT-4, Lung Cancer HOP-92, Colon Cancer HCC-2998, CNS Cancer SNB-75, Melanoma SK-MEL-2, Ovarian Cancer IGROV1, Renal Cancer 786-0, RXF 393, Breast Cancer HS 578T and T-47D (GI50: 1.00-2.71μM). Moreover, enzyme assays were carried out to investigate the possible antiproliferative mechanism of action of compound 4c. The results revealed that compound 4c has good c-Src inhibitory activity at 10μM. In addition, molecular docking studies showed that 4c could bind to the ATP Src pocket sites. Fulfilling the Lipinskiís rule of five in addition to its ADME profile and the biological results, all strongly suggest that 4c is a promising Src kinase inhibitor.

A Direct Route to a New Class of Acrylamide Thioglycosides

The preparation of a new class of acrylamide thioglycosides via one‐pot reaction of the potassium 2‐cyanoethylene‐1‐thiolate salts with 2,3,4,6‐tetra‐O‐acetyl‐α‐D‐gluco‐ and galactopyranosyl bromides has been studied. The E‐configuration of these thioglycosides was proven by their transformations to the corresponding 5‐aminopyrazoles.

Design, synthesis, antimicrobial evaluation and molecular docking studies of some new 2,3-dihydrothiazoles and 4-thiazolidinones containing sulfisoxazole

Abstract Microbial resistance to the available drugs poses a serious threat in modern medicine. We report the design, synthesis and in vitro antimicrobial evaluation of new functionalized 2,3-dihydrothiazoles and 4-thiazolidinones tagged with sulfisoxazole moiety. Compound 8d was most active against Bacillis subtilis (MIC, 0.007 µg/mL). Moreover, compounds 7c–d and 8c displayed significant activities against B. subtilis and Streptococcus pneumoniae (MIC, 0.03–0.06 µg/mL and 0.06–0.12 µg/mL versus ampicillin 0.24 µg/mL and 0.12 µg/mL; respectively). Compounds 7a and 7c–d were highly potent against Escherichia coli (MIC, 0.49–0.98 µg/mL versus gentamycin 1.95 µg/mL). On the other hand, compounds 7e and 9c were fourfolds more active than amphotericin B against Syncephalastrum racemosum. Molecular docking studies showed that the synthesized compounds could act as inhibitors for the dihydropteroate synthase enzyme (DHPS). This study is a platform for the future design of more potent antimicrobial agents.

Novel Diastereoselective Synthesis and X-Ray Crystallographic Studies of (E)-2-cyano-N-(4-ethoxyphenyl)-3-methylthio-3-(substituted-amino)Acrylamides

Three derivatives of the novel (E)-2-cyano-N-(4-ethoxyphenyl)-3-methylthio-3-(substituted-amino)acrylamides 3–5 were selectively synthesized by the one-pot reaction of 2-cyano-N-(4-ethoxyphenyl)acetamide (2) with substituted isothiocyanates and methyl iodide in DMF containing potassium hydroxide as a basic catalyst. The stereochemistry and the structures of the synthesized compounds were confirmed by single crystal X-ray diffraction, IR, 1H-NMR, 13C-NMR, mass spectroscopy, and elemental analyses.

A Comparative Study of Smart Spectrophotometric Methods and a Densitometric Method for Simultaneous Determination of Binary Mixture of Canagliflozin and Metformin Hydrochloride

Abstract Simple and sensitive Spectrophotometric methods and a densitometric thin layer chromatographic method (TLC) are developed and validated for simultaneous determination of binary mixture of metformin hydrochloride (MET) and canagliflozin (CFZ) in combined dosage form. Three spectrophotometric methods manipulating ratio spectra namely ratio subtraction, ratio difference and derivative ratio are used for the determination of MET in the presence of CFZ without preliminary separation, while CFZ is directly determined by measuring its absorbance at λmax 290 nm. The calibration curves follow Beers law in the concentration range of 1 - 20 and 1 - 30 μg/mL for MET and CFZ respectively. A simple TLC method is developed where separation is performed on TLC silica gel plates 60F254 using toluene: Methylene chloride: methanol: water: glacial acetic acid in the volume ratio (20:15:15:1:0.25) as a mobile phase. Rf values are 0.55 ± 0.05 for CFZ and 0.21 ± 0.03 for MET, the linearity ranges are 0.3-4.5 and 0.5-5.5 μg/band for CFZ and MET respectively. The developed methods are successfully applied for the simultaneous determination of MET and CFZ in bulk and pharmaceutical formulation.