Design, synthesis and anticervical cancer activity of new benzofuran-pyrazol-hydrazono- thiazolidin-4-one hybrids as potential EGFR inhibitors and apoptosis inducing agents.

This study represents the synthetic approaches of a new set of 2-(((3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazono)-5-(aryl)thiazolidin-4-one derivatives 4-22 aiming to obtain new antiproliferative candidates against human cervix carcinoma cells (Hela) of EGFR PK inhibiting potency. The cancer cells represented promising sensitivity towards the compounds 6, 7, 11, 13, 14, 16, 17 more than or equal to that against the reference drug doxorubicin. In addition, the latter compounds were tested as EGFR protein kinase inhibitors. The results revealed that compound 14 showed more significant EGFR PK inhibitory activity than the reference drug erlotinib (IC50; 0.07, 0.08 µM, respectively). Moreover, cell cycle analysis and apoptosis assay were performed for compound 14 proving its ability to cause G1/S phase arrest and apoptosis in Hela cancer cells, in addition to its activation of the caspases-7 and -3. In addition, derivative 14 increased the expression level of p53 and the ratio of Bax/Bcl-2 which confirmed its mode of action. Molecular docking study of 14 was performed to investigate its binding mode of interaction with EGFR PK in the active site with the aim of rationalizing its promising inhibitory activity. Accordingly, compound 14 might be considered as a promising scaffold anticervical cancer chemotherapeutic and deserves further optimization and in-depth biological studies.

Synthesis, In Vitro Antimicrobial and Cytotoxic Activities of Some New Pyrazolo[1,5-a]pyrimidine Derivatives.

A new series of pyrazole 4⁻7 and pyrazolo[1,5-a]pyrimidine 8⁻13 were synthesized by using a simple, efficient procedure, and screened for their in-vitro antimicrobial and antitumor activities. Symmetrical and asymmetrical 3,6-diarylazo-2,5,7-triaminopyrazolo[1,5-a]pyrimidine were synthesized by the conventional method and also subjected to microwave irradiation and under ultrasound conditions. The biological results revealed that most of the tested compounds proved to be active as antibacterial and antifungal agents. The antitumor activity of the synthesized compounds was evaluated against human cancer cell lines, MCF-7, HCT-116, and HepG-2, as compared with Doxorubicin as a control.

SYNTHESIS AND BIOLOGICAL EVALUATION OF SULFONAMIDE DERIVATIVES AS ANTIMICROBIAL AGENTS.

The present study investigates, the synthesis of new derivatives of benzenesulfonamide nucleus hybridized with various substituted pyrazole 4, 8 and thiazole ring 6 using 4-amino-N-butylbenzenesulfonamide 1 as the key starting compound. Furthermore, 3,5-diaminopyrazole derivative 10 was allowed to react with different reagents such as an active methylene compounds, ketone dithioacetal, ethoxymethylene malononitrile and cyanoguanidine for a preparation of new benzenesulfonamide derivatives 11-18 conjugated with different substituted hetero-bicyclic ring systems. In vitm-antimicrobial evaluation was performed for most of the newly synthesized compounds using ciprofloxacin and Fluconazole as antibacterial and antifungal standard drugs, respectively The most promising dual antibacterial and antifungal potency was gained by the sulfamoylphenyl butenoic acid derivative 7, followed by the sulfamoylphenyl-2-chloroacetamide 5 and its heterocyclic pyrazolopyrimidine derivative 16. Further development and structural optimization will be carried out to get new more potent and safer antimicrobials.

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF 2,3-DISUBSTITUTED AND FUSED QUINOXALINES AS POTENTIAL ANTICANCER AND ANTIMICROBIAL AGENTS.

This article describes the synthesis of new bioactive quinoxalines as potential anticancer and antimicrobial agents; 2,3-dichloroquinoxaline was used as the key molecule for the preparation of various mono or disubstituted quinoxalines 2-7, pyridoimidazoquinoxaline derivative 8, thiazolo[4,5-b]quinoxaline derivatives 9-11, piperazinoquinoxaline derivatives 12, 13 and 1,4-benzoxazino[2,3-b]quinoxaline 15. The newly synthesized compounds were evaluated for their anticancer and antimicrobial activity. Assay results showed the compounds 6-bromo-2-chloro-N-[4-(trifluoromethyl)phenyl]-3-aminoquinoxaline (4), 7-bromo-2-[2-(4-methoxy-benzylidene) hydrazinyl]thiazolo[5,4-b]quinoxaline (9d) and 7-bromo-1,2,3,4-tetrahydropyrazino[2,3- blquinoxaline (12) proved to possess dual effects as potential anti-cancer and antimicrobial agents.

SYNTHESIS, BIOLOGICAL EVALUATION AND MOLECULAR DOCKING STUDIES OF AROMATIC SULFONAMIDE DERIVATIVES AS ANTI-INFLAMMATORY AND ANALGESIC AGENTS.

In this study, [4-(N-substituted sulfamoyl)phenyl]carbonohydrazonoy dicyanides 3a-c were synthesized and condensed with various hydrazine hydrate derivatives to produce the corresponding 3,5-diaminopyrazole derivatives 4-9, respectively. Furthermore, condensation of 3b with ax-naphthol, urea and thiourea yielded the pyrimidine derivatives 10 and 11a,b, respectively. Also, condensation of 3b with hydroxylamine hydrochloride produced the isoxazole derivative 12. Treatment of 3b with different secondary amines afforded the piperidine and piperazine derivatives 13a-c, respectively, while its condensation with diamines yielded the corresponding diazepine, benzodiazepine and benzooxazepine derivatives 14-16. Reaction of 3b with malononitrile or diazonium salt 2b with MND followed by treatment with malononitrile afforded the pyrido-pyridazine derivative 18. Anti-inflammatory and analgesic evaluation of some of the synthesized compounds as representative examples exhibited equipotent activity to that of the reference drug celecoxib. The ulcerogenic potential of the tested derivatives showed a complete safety profile on G.I.T. system. Molecular docking studies showed that the tested compounds induced good fitting and forming different hydrogen bonds with the amino acid residues at the active sites of COX-2 enzyme.

Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anticancer activity as inhibitors of c-Met kinase.

In an effort to develop potent anti-cancer agents, we have synthesized some substituted quinoxaline derivatives. Reaction of 6-bromo-3-methylquinoxalin-2(1H)-one 1 with aromatic aldehydes furnished the styryl derivatives 2a-e. Alkylation of 1 with ethyl chloroacetate produced the N-alkyl derivatives 3. Hydrazinolysis of the ester derivative 3 with hydrazine hydrate afforded the hydrazide derivative 4. In addition, chlorination of 1 with phosphorus oxychloride afforded the 2-chloro derivative 5 which was used as a key intermediate for the synthesis of substituted quinoxaline derivatives 6-8, N-pyrazole derivative 9, tetrazolo[1,5-a]quinoxaline derivative 10 and Schiff base derivatives 13, 15 via reaction with several nucleophiles reagents. Docking methodologies were used to predict their binding conformation to explain the differences of their tested biological activities. All the tested compounds were screened in vitro for their cytotoxic effect on three tumor cell lines. Some new quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. Compounds 2e, 4, 7a, 12a, 12b and 13 showed the highest binding affinity with CDOCKER energy score, while showed the lowest IC50 values against three types of cancer cell lines. It is worth to mention that, compounds 2e, 7a, 12b and 13 showed comparable inhibition activity to the reference drug, while compounds 4 and 12a showed a more potent inhibition activity than Doxorubicin.

Synthesis, Characterization and Biological Evaluation of Some Quinoxaline Derivatives: A Promising and Potent New Class of Antitumor and Antimicrobial Agents.

In continuation of our endeavor towards the development of potent and effective anticancer and antimicrobial agents; the present work deals with the synthesis of some novel tetrazolo[1,5-a]quinoxalines, N-pyrazoloquinoxalines, the corresponding Schiff bases, 1,2,4-triazinoquinoxalines and 1,2,4-triazoloquinoxalines. These compounds were synthesized via the reaction of the key intermediate hydrazinoquinoxalines with various reagents and evaluated for anticancer and antimicrobial activity. The results indicated that tetrazolo[1,5-a]quinoxaline derivatives showed the best result, with the highest inhibitory effects towards the three tested tumor cell lines, which were higher than that of the reference doxorubicin and these compounds were non-cytotoxic to normal cells (IC50 values > 100 µg/mL). Also, most of synthesized compounds exhibited the highest degrees of inhibition against the tested strains of Gram positive and negative bacteria, so tetrazolo[1,5-a]quinoxaline derivatives show dual activity as anticancer and antimicrobial agents.

New sulfonamide-based glycosides incorporated 1,2,3-triazole as cytotoxic agents through VEGFR-2 and carbonic anhydrase inhibitory activity.

New sulfonamide-triazole-glycoside hybrids derivatives were designed, synthesised, and investigated for anticancer efficacy. The target glycosides' cytotoxic activity was studied with a panel of human cancer cell lines. Sulfonamide-based derivatives, 4, 7 and 9 exhibited promising activity against HepG-2 and MCF-7 (IC50 = 8.39-16.90 µM against HepG-2 and 19.57-21.15 µM against MCF-7) comparing with doxorubicin (IC50 = 13.76 ± 0.45, 17.44 ± 0.46 µM against HepG-2 and MCF-7, rescpectively). To detect the probable action mechanism, the inhibitory activity of these targets was studied against VEGFR-2, carbonic anhydrase isoforms hCA IX and hCA XII. Compoumds 7 and 9 gave favorable potency (IC50 = 1.33, 0.38 µM against VEGFR-2, 66, 40 nM against hCA IX and 7.6, 3.2 nM against hCA XII, respectively), comparing with sorafenib and SLC-0111 (IC50 = 0.43 µM, 53 and 4.8 nM, respectively). Moreover, the docking simulation was assessed to supply better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes that was used for further modification in the anticancer field.

A concise synthesis and antimicrobial activity of a novel series of naphthylpyridine-3-carbonitrile compounds.

A novel series of acyclic nucleosides 2-5 and 13a-c were synthesized by utilizing 4-phenyl-6(naphthalen-2-yl)-2-oxo-1,2-dihydropridine-3-carbonitrile (1) as a key starting material. Chlorination of 1 yielded the chloro analogue 6 that was allowed to react with urea, thiourea, thiosemicarbazide and alicyclic secondary amines to produce the corresponding derivatives 7a-c and 11a-c. Further condensation of 6 with various amino acids provided the compounds 8-10, whereas hydrazinolysis of 6 yielded the hydrazinyl analogue 12 which was condensed with different isothiocyanates and acid anhydrides to afford derivatives 18-20, respectively. Upon treatment of 12 with sodium nitrite, the azide derivative 14 was obtained which was subjected to reaction with various active methylene compounds to obtain the corresponding triazolo derivatives 15-17. The structure assignment of the new compounds is based on chemicaland spectroscopic evidence. Antimicrobial evaluation of the newly synthesized derivatives was performed using ciprofloxacin and fluconazole as reference antibacterial and antifungal drugs. The most effective compounds against the tested bacterial and fungal isolates were the benzothiohydrazide compound 18b followed by the hydrazone and the phthalic anhydride derivatives 13c and 20, respectively.

Synthesis and evaluation of analgesic, anti-inflammatory and ulcerogenic activities of some triazolo- and 2-pyrazolyl-pyrido[2,3-d]-pyrimidines.

New series of 2-hydrazino-7,8-dihydro-6H-cyclopenta[5,6] pyrido[2,3-d]pyrimidines and its 1,7,8,9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine, 1,7,8,9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,3,4]tetrazolo[4,5-a]pyrimidine, 8,9-dihydro-7H-cyclopenta[5,6]pyrido[2,3-d]imidazolo[1,2-a]pyrimidine, 2-(pyrazol-1-yl)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine derivatives were prepared in order to obtain new compounds with potential anti-inflammatory and analgesic activity and low ulcerogenic effect. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic and ulcerogenic activities. Compounds 3-amino-6-(4-aryl)-9-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(H)-one (4c), 1-amino-2-methyl-6-(4-aryl)-9-(4-aryl-methylene)-cyclopenta[5,6]pyrido[2,3-d]imidazolo[1,2-a]pyrimidin-5(H)-one (6a), 2-amino-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]pyrido-[2,3-d]pyrimidine-4(H)-one (9), 2-(3-amino-5-hydroxypyrazol- 1-yl)-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]-pyrido[2,3-d]pyrimidin-4(H)-one (10a) and 3-thioxo-6-(4-aryl)-9-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d]-[1,2,4]triazolo[4,3-a]pyrimidin-5(H)-one (13) showed significant analgesic effects. Compound 2-(3-amino-5-hydroxypyrazol-1-yl)-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta [5,6]pyrido[2,3-d]pyrimidin-4(H)-one (10a) was evaluated as the lead compound having higher anti-inflammatory activity (82.8%) than ibuprofen (79.5%) and lower ulcerogenic effect.

Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel pyrimidoquinolines and its nucleoside derivatives.

Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[4',3':-1,2]pyrimido[4,5-b]quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[4',3':1,2]-pyrimidoquinoline (5a,b, 10), imidazolo[3',2':1,2]pyrimido[4,5-b]-quinoline (8a,b), 6-chloro-2-methylthiopyrimido[4,5-b]quinoline (12), acetylated nucleosides (16, 17a,b) and deacetylated nucleosides (18, 19a,b). Some of the novel pyrimidoquinoline derivatives possess highly activity toward the bacteria and fungi species. The new quinolines derivatives were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having LD(50) values in the low micromolar to nanomolar concentration range.

Synthesis and antimicrobial activity of new 1-[(tetrazol-5-yl)methyl] indole derivatives, their 1,2,4-triazole thioglycosides and acyclic analogs.

New 1-[(tetrazol-5-yl)methyl]indole derivatives, their acyclic nucleoside analogs and the corresponding glycoside derivatives were synthesized. Furthermore, the [)(1,2,4-triazol-3-yl)methyl])-2H-tetrazole derivative as well as the corresponding thioglucoside were prepared. The synthesized compounds were tested for their antimicrobial activity against Aspergillus Niger, Penicillium sp, Candida albican, Bacillus subtilis, Streptococcus lacti, Escherichia coli, Pseudomonas sp., and streptomyces sp. Compounds 3, 5 and 19b exhibited potent antibacterial activity and compounds 4, 5 and 10 exhibited high activities against the tested fungi compared with fusidic acid.

Synthesis and antitumor activity of new dihydropyridine thioglycosides and their corresponding dehydrogenated forms.

A number of a new pyridine thioglycosides were synthesized via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-alpha-D-gluco- and galactopyranosyl bromide. The antitumor activities of the synthesized compounds were evaluated utilizing two different human cell lines. Some of the tested compounds showed high inhibition of human cell lines. The detailed synthesis, spectroscopic data and antitumor activities for the synthesized compounds were reported.

Antimicrobial activity of some synthesized glucopyranosyl-pyrimidine carbonitrile and fused pyrimidine systems.

3-Amino-5-(4-chlorophenylamino)-4-cyanofuran-2-carboxamide (2) was used as the key molecule for preparation of various furopyrimidines 3-9 and formation of spiro-cycloalkane furopyrimidines 10, 11. Also, poly fused heterocyclic compounds 13-17 were prepared from compound 2. The synthesized compounds were screened for their antimicrobial activity.

S- and C-nucleosidoquinazoline as new nucleoside analogs with potential analgesic and anti-inflammatory activity.

Thioglycosides and C-glycosides have received considerable attention, because they are widely employed as biological inhibitors, inducers and ligands for affinity chromatography of carbohydrate-processing enzymes and proteins. Moreover, they are promising candidates in synthetic carbohydrate chemistry as convenient and versatile glycosyl donors. Among these glycosyl donors are the thioglycosyl and N-glycosyl heterocycles that are sufficiently stable under a variety of reaction conditions and have the ability to be readily converted into a variety of other functionalities. We report here, the synthesis of 2-thioxo-quinazolines 1a-c which were used as a base to the synthesis of S-nucleoside of types 10, 11 and acyclic C-nucleoside analogs of type 14 and their analgesic and anti-inflammatory activities were evaluated giving good results.