Synthesis of New of 4-Thiazolidinone and Thiazole Derivatives Containing Coumarin Moiety with Antimicrobial Activity.

Synthesizing hybrid molecules is one the best manner to achieve novel promising agents. Consequently, series of new thiazoles having coumarin nucleus were synthesized from 3-acetylcoumarin thiosemicarbazones. Cyclization of thiosemicarbazone derivatives with ethyl 2-chloroacetate, 1-chloropropan-2-one and 2-bromo-1-phenylethanone afforded the corresponding 4-thiazolidinones, 4-methylthiazoles and 4-phenylthiazoles, respectively. The expected antimicrobial propriety for the synthesized thiosemicarbazone and thiazole derivatives were investigated. The thiosemicarbazones and thiazolidin-4-ones showed moderate activities against G +ve and G -ve bacteria.

Novel Structural Hybrids of Pyrrole and Thiazole Moieties: Synthesis and Evaluation of Antibacterial and Antifungal Activities.

One of the best ways to design new biocidal agents is synthesizing hybrid molecules by combining two or more bioactive moieties in a single molecular scaffold. So, new series of pyrroles bearing a thiazole moiety were synthesized using 1-methyl-1H-pyrrole-2-carbaldehyde thiosemicarbazones 1a-c. Cyclization of thiosemicarbazone derivatives 1a-c with ethyl chloroacetate, ethyl 2-chloropropanoate, chloroacetone and phenacyl bromide afforded the corresponding thiazolidin-4-ones 2a-c, 5-methylthiazolidin-4-ones 3a-c, 4-methyl-2,3-dihydrothiazoles 4a-c, and 4-phenyl-2,3-dihydrothiazoles 5a-c, respectively. The antimicrobial activity of the new thiazole derivatives was evaluated.

Synthesis and hyperglycemic, biochemical and histopathological evaluation of novel sulfonylbiguanide and sulfonylurea derivatives as potent anti-diabetic agents.

New sulfonylbiguanide hydrochloride salts and sulfonylurea derivatives containing two sulfonyl groups were synthesized through the reaction of arylsulfonohydrazides with cyanoguanidine and p-tolylsulfonylisocyanate, respectively. Oral treatment of hyperglycemic rats with the synthesized sulfonylbiguanide derivatives 2 and sulfonylurea derivatives 3 revealed that sulfonylurea derivatives 3a and 3c possessed significant decrease of the elevated glucose in compression with the anti-diabetic standard drugs. Effects of the synthesized sulfonylurea derivatives 3a and 3c on the diabetic properties towards α-amylase, liver function enzyme levels (AST, ALT, ALP, TB and γ-GT), kidney functions (urea and creatinine), lipids profiles (TG, TL, TC and HDL-C) were studied. Also, the effect of sulfonylurea derivatives 3a and 3c as antioxidants (reduced glutathione and lipid peroxide) was evaluated. Histopathological examination of hepatic and pancreatic tissues was investigated. The obtained results suggested that the most potent sulfonylurea derivatives 3a and 3c might be possible used as novel diabetic inhibitor agents.

Novel structural hybrids of quinoline and thiazole moieties: Synthesis and evaluation of antibacterial and antifungal activities with molecular modeling studies.

One of the best ways to design new biocidal agents is synthesizing hybrid molecules by combining two or more bioactive moieties in a single molecular scaffold. So, new series of quinolines bearing a thiazole moiety were synthesized using thiosemicarbazones 2a-f. Cyclization of 2a-f with ethyl chloroacetate, ethyl 2-chloropropanoate or chloroacetone afforded the corresponding thiazoles 3-5. The antimicrobial activity of the new quinoline derivatives was evaluated. The most of tested compounds revealed potent both of the antibacterial and antifungal activities. Fourfold potency of amphotericin B for the inhibition the growth of the A. fumigatus was displayed by ccompound 5e. The latter compound displayed twofold potency of gentamycin for inhibition the growth of N. gonorrhoeae. Moreover, this compound showed equipotent potency of references drugs for inhibition of the growth of S. flexneri, S. pyogenes, P. vulgaris, A. clavatus, G. candidum and P. marneffei. So, quinolines bearing a thiazole moiety can be suggested as interesting scaffolds for the development both of the novel antibacterial and antifungal agents. Some new derivatives were studied as peptide deformylase enzyme inhibitors. Thiazolidin-4-one derivative 3d and 2,3-dihydrothiazole derivative 5c had shown good PDF inhibition activity, which had been supported by the docking results with highest binding affinity and lowest docking energy score. These results suggested that the most potent compounds might be possible agents as novel bacterial PDF inhibitor.

Synthesis and Evaluation of 5-imino-4-thioxoimidazolidin-2-one Derivatives as Antibacterial and Antifungal Agents.

OBJECTIVE: It was interesting to synthesize some new 5-imino-4-thioxoimidazolidin-2- one derivatives with different halogenated and alkylated aromatic substituents at N-(1) and N-(3) and evaluation of their expected antibacterial and antifungal activities. METHODS: New 5-imino-4-thioxoimidazolidin-2-one derivatives were synthesized through the reaction of different halogenated and alkylated N-arylcyanothioformamides with halogenated and alkylated aryl isocyanates. RESULTS: 5-Imino-4-thioxoimidazolidin-2-ones were obtained in high yields with excellent purity. The activities of imidazolidines as antibacterial and antifungal agents were studied. Some of the imidazolidine derivatives displayed significant antibacterial and antifungal activities. CONCLUSION: 5-Imino-4-thioxoimidazolidin-2-ones were obtained in 77-90% yields with excellent purity. The antibacterial and antifungal activities suggest that some of the imidazole derivatives possess significant antimicrobial activity against B. subtilis, K. pneumonia and C. albicans and moderate activity against S. aureus.

Synthesis and anticancer activity of thiourea derivatives bearing a benzodioxole moiety with EGFR inhibitory activity, apoptosis assay and molecular docking study.

New thiourea derivatives bearing a benzodioxole moiety were synthesized via the reaction of 5-isothiocyanatobenzodioxole with amino compounds such as aromatic amines, sulfa drugs, heterocyclic amines, hydrazines and hydrazides. The anticancer activity of the synthesized thiourea derivatives was examined against HCT116, HepG2 and MCF-7 cancer cell lines. Most of thiourea derivatives revealed significant cytotoxic effect, in some cases greater than the doxorubicin. As example, IC50 values of N1,N3-disubstituted-thiosemicarbazone 7 were 1.11, 1.74 and 7.0 µM for HCT116, HepG2 and MCF7, respectively; IC50 values of doxorubicin were 8.29, 7.46 and 4.56 µM, respectively. The anticancer mechanisms were studied via EGFR inhibition and apoptosis assessments, as well as molecular docking.

Synthesis, structural characterization and in vivo anti-diabetic evaluation of some new sulfonylurea derivatives in normal and silicate coated nanoparticle forms as anti-hyperglycemic agents.

Series of new sulfonylurea derivatives (gliclazide analogues) was synthesized and characterized. Thus, p-tolylsulfonylisocyanate was left to react with different amino derivatives under mild conditions to afford the desired sulfonylurea derivatives 1-5. The molecular structure of the compound N-(2,6-Dichlorophenylcarbamoyl)-4-methylbenzenesulfonamide, 1c has been elucidated by single crystal X-ray diffraction. Anti-diabetic properties of the synthesized compounds relative to anti-diabetic drug (gliclazidem MR60) were carried out, where most of the tested compounds showed significant activity for reducing the blood glucose level. The results revealed that compounds 1c and 5 showed better anti-diabetic activities compared with gliclazide. Activity of the most potent derivatives of sulfonylurea compounds namely 1c and 5 were increased using coated nanostructure tetraethyl orthosilicate (TEOS) as a modified release (MR) agent. The effect of the prepared sulfonylurea compounds against the diabetic condition was investigated using specific selected biomarkers as of liver enzyme activities as transaminases (AST, ALT) and alkaline phosphatase (ALP), lipids profiles; total cholesterol (TC), triacylglycerols (TG) and total lipid (TL). The antioxidants, oxidative stress biomarkers and histological examination were also examined and discussed.

Synthesis and anticancer activity of bis-benzo[d][1,3]dioxol-5-yl thiourea derivatives with molecular docking study.

New thiourea derivatives incorporating two benzo[d][1,3]dioxol-5-yl moieties have been synthesized through the reaction of two molecules of benzo[d][1,3]dioxol-5-yl isothiocyanate with one molecule of various diamino derivatives. The synthesized compounds were examined for their cytotoxic effects using SRB assay on three cancer cell lines HepG2, HCT116 and MCF-7. Most of compounds showed significant antitumor activity and some compounds showed strong results greater than the reference drug. As example, IC50 values of 1,1'-(1,4-phenylene)bis(3-(benzo[d][1,3]dioxol-5-yl)thiourea) 5 were 2.38 µM for HepG2, 1.54 µM for HCT116 and 4.52 µM for MCF7, while the IC50 values of standard drug doxorubicin were 7.46, 8.29 and 4.56 µM, respectively. Interestingly, these compounds were non cytotoxic toward the tested normal cell line (IC50 value > 150 µM). The anticancer mechanisms were studied via EGFR inhibition assessment, annexin V-FITC apoptosis assessment, cell cycle analysis and study the effect on mitochondrial apoptosis pathway proteins Bax and Bcl-2 as well as molecular docking studies.

5-Thioxoimidazolidine-2-one derivatives: Synthesis, anti-inflammatory activity, analgesic activity, COX inhibition assay and molecular modelling study.

A series of 5-imino-4-thioxo-2-imidazolidinone derivatives with different substituents at N1 and N3 was synthesized with high yield and excellent purity by the reaction of different N-arylcyanothioformamide derivatives with isocyanate derivatives. Treatment 5-imino-4-thioxo-2-imidazolidinone derivatives with acidic medium afforded 4-thioxoimidazolidin-2,5-dione derivatives. The structures of the obtained products were established based on spectroscopic IR, 1H NMR, 13C NMR, 1H, 1H-COSY, HSQC and elemental analyses. The anti-inflammatory activity of the synthesized compounds through the carrageenan-paw edema model as well as in vitro COX-1 and COX-2 inhibition assay were evaluated where most of the synthesized compounds showed significant anti-inflammatory activity. Mostly, all of our synthesized compounds have greater activity more than celecoxib toward both cyclooxygenase enzymes. All of the tested compounds (except one compound) exhibited IC50 valves for COX-2 ranged from 0.001 × 10-3 to 0.827 × 10-3 µM while the reference drug has IC50 40.0 × 10-3 µM. Furthermore, the analgesic activity of such compounds was also determined. Molecular modeling study was also conducted to rationalize the potential as anti-inflammatory agents of our synthesized compounds by predicting their binding modes, binding affinities and optimal orientation at the active site of the COX enzymes.

Design, synthesis, antiproliferative activity, molecular docking and cell cycle analysis of some novel (morpholinosulfonyl) isatins with potential EGFR inhibitory activity.

New series of 5-(morpholinosulfonyl) isatin derivatives were designed and synthesized. The new compounds were characterized on the basis of spectral and elemental analyses. They were examined for their cytotoxic effects using SRB assay on four cancer cell lines HepG2, HCT116, CACO and MCF-7 in addition to the non-cancerous human cell line. They were non cytotoxic towards the normal derived cell line (IC50 value > 130 µM). Compounds 3, 6, 10 and 11 showed IC50 values less than 10 µM on three of the tested cell lines HepG2, HCT116 and CACO. Compounds 2h, 5, and 7b showed IC50 values less than or nearly equal 10 µM on HepG2, CACO and HCT116 respectively. Compounds 3 and 6 revelaed IC50 values less than 12 µM on MCF7. These obtained IC50 values are comparable with that of doxrubicin as it has showed IC50 range from 4.5 to 8.28 µM on the tested cell lines. All these promising derivatives showed inhibitory activity against EGFR with IC50 values less than 2 µM. The most potent EGFR inhibitors 7b (IC50 = 46 nM) and 10 (IC50 = 23 nM) showed to cause cell cycle arrest at G2/M phase and induce apoptosis. Molecular docking studies also were simulated to put insight and make better understanding to their structural features.

1,6-Addition of Tertiary Carbon Radicals Generated From Alcohols or Carboxylic Acids by Visible-Light Photoredox Catalysis.

The addition of tertiary carbon radicals generated by an Ir-catalyzed visible-light photocatalyst to electron-deficient 1,3-dienes proceeds in good yields to append a δ-substituted ß,γ-unsaturated carbonyl fragment to a tertiary alcohol or carboxylic acid precursor and construct a new quaternary carbon center.

Quinoline derivatives bearing pyrazole moiety: Synthesis and biological evaluation as possible antibacterial and antifungal agents.

In an attempt for development of new antimicrobial agents, three series of quinoline derivatives bearing pyrazole moiety have been synthesized. The first series was synthesized through the synthesis of 4-(quinolin-2-yloxy)benzaldehyde and 4-(quinolin-2-yloxy)acetophenone and then treatment with ketone or aldehyde derivatives to afford the corresponding chalcones. Cyclization of the latter chalcones with hydrazine derivatives led to the formation of new pyrazoline derivatives. The second series was synthesized via the synthesis of 2-hydrazinylquinoline and then treatment with formylpyrazoles to afford the corresponding hydrazonyl pyrazole derivatives. The third series was synthesized through the treatment of 2-hydrazinylquinoline with ethoxyethylidene, dithioacetal and arylidene derivatives to afford the corresponding pyrazole derivatives. The synthesized compounds were evaluated for their expected antibacterial and antifungal activities; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Pyrazole derivative 13b showed better results when compared with the reference drugs as revealed from their MIC values (0.12-0.98 µg/mL). The pyrazole derivative 13b showed fourfold potency of gentamycin in inhibiting the growth of S. flexneri (MIC 0.12 µg/mL). Also, compound 13b showed fourfold potency of amphotericin B in inhibiting the growth of A. clavatus (MIC 0.49 µg/mL) and C. albicans (MIC 0.12 µg/mL), respectively. The same compound showed twofold potency of gentamycin in inhibiting the growth of P. vulgaris (MIC 0.98 µg/mL), equipotent to the ampicillin and amphotericin B in inhibiting the growth of S. epidermidis (MIC 0.49 µg/mL), A. fumigatus (MIC 0.98 µg/mL), respectively. Thus, these studies suggest that quinoline derivatives bearing pyrazole moiety are interesting scaffolds for the development of novel antibacterial and antifungal agents.

New Biguanides as Anti-Diabetic Agents, Part II: Synthesis and Anti-Diabetic Properties Evaluation of 1-Arylamidebiguanide Derivatives as Agents of Insulin Resistant Type II Diabetes.

New 1-arylamidebiguanide hydrochloride salts were synthesized via reaction of hydrazide derivatives with dicyandiamide in acidic medium. The structure of the obtained derivatives was characterized by spectroscopic and elemental analysis tools. The anti-diabetic properties of the synthesized compounds were determined. Oral treatment of hyperglycemic rats with the synthesized biguanide derivatives showed a significant decrease of the elevated glucose in comparison with the anti-diabetic standard drug, metformin. The effects of the synthesized biguanide derivatives on the diabetic properties regarding liver function enzyme activities (AST, ALT, and ALP), lipid profiles (TC, TG, and TL), lipid peroxide, and nitrous oxide as well as histopathological characteristics were investigated and discussed.

New Biguanides as Anti-Diabetic Agents Part I: Synthesis and Evaluation of 1-Substituted Biguanide Derivatives as Anti-Diabetic Agents of Type II Diabetes Insulin Resistant.

New 1-substituted-biguanide hydrochloride salts were synthesized via reacting benzo[1,3-d]dioxol-5-amine, phenylhydrazine, N,N-dimethylhydrazinecarboxamide, benzohydrazide and 2-phenyl acetohydrazide with dicyandiamide in acidic medium. Structures of the obtained biguanide salts were characterized by spectroscopic tools. The synthesized compounds were screened for their anti-diabetic activity with standard metformin drug. Oral treatment of hyperglycemic rats with the synthesized biguanide derivatives significantly decreased the elevated blood glucose level. Additionally, anti-diabetic properties towards liver function enzyme activities (AST, ALT and ALP), lipids profiles (TC, TG and TL), lipid peroxide and nitrous oxide as well as histopathological studies relative to metformin hydrochloride were investigated and discussed.

New Imidazolidineiminothione, Imidazolidin-2-one and Imidazoquinoxaline Derivatives: Synthesis and Evaluation of Antibacterial and Antifungal Activities.

A series of new 5-imino-4-thioxo-2-imidazolidinone derivatives 3 with various halogenated and alkylated aromatic substituents at N1 and N3 was synthesized. Imidazolidineiminothione derivatives 3 were prepared from the reaction of N-arylcyanothioformamide derivatives with aryl isocyanates. These compounds were used as key synthons for the preparation of wide variety of new substituted imidazole compounds. Imine hydrolysis of 3 with ethanolic HCl produced the corresponding 4-thioxo-2,5-imidazolidindiones 4. Condensation of 3 with benzophenonhydrazone furnished the corresponding 4-azine derivatives 5. Monohydrazono and dihydrazono derivatives 6 and 8 were obtained upon treatment of imidazolidinone derivatives 3 with hydrazine hydrate. Finally, imidazolidinones 3 were reacted with o-phenylenediamines or pyrazol-5(4H)-ones and afforded the corresponding imidazoquinoxaline and imidazolidin-4-ylidenepyrazolone-5(4H)-one derivatives 11 and 12, respectively. Evaluation of the antibacterial and antifungal activities for the synthesized compounds was carried out to probe their activities. Most of the tested compounds showed significant activities. The best antimicrobial activity was observed for 1-(3-ethoxyphenyl)-6-methyl-1-phenyl-1H-imidazo[4,5-b]quinoxalin-2(3H)-ones (11c) followed by 5-imino-3-(3-methoxy- phenyl)-1-phenyl-4-thioxoimidazolidin-2-one (3f).

New imidazolidineiminothione derivatives: Synthesis, spectral characterization and evaluation of antitumor, antiviral, antibacterial and antifungal activities.

A series of new imidazolidineiminothione derivatives with various halogenated and alkylated aromatic substituents at N-(1) and at N-(3) was synthesized through the reaction of N-arylcyanothioformamides with arylisocyanate derivatives. Structure of imidazolidineiminothione derivatives were established based on spectroscopic IR, (1)H NMR, (13)C NMR, (1)H,(1)H-COSY, HSQC, (19)F NMR, MS and elemental analyses data. Evaluation of antitumor, antiviral, antibacterial and antifungal activities for the synthesized compounds were carried out to probe their activities. Most of the synthesized compounds displayed antitumor activity. The presence of 3,5-dichlorophenyl moiety at N-(1) and trichlorophenyl moiety on N-(3) (2f) resulted the highest cytotoxic activity. The presence of 9H-fluorenyl moiety on N-(3) resulted in the lowest cytotoxic activity. The antiviral screening displayed that 2d and 2f were markedly active against one or two viral strains. Compound 2d (3,5-dichlorophenyl moiety at N-(1) and 4-chlorophenyl moiety on N-(3)) showed 100% antiviral effect toward HAV. Compound 2f showed 96.7% antiviral effect toward HSV1 and 80.3% antiviral effect toward HAV. The antimicrobial activity suggested that all of the imidazolidineiminothione derivatives possess significant antimicrobial activity against most of the test organisms. Some imidazolidineiminothione derivatives showed MIC values of antibacterial and antifungal activities ranged from 0.78 to 6.25 µg/ml.

Synthesis of thiosemicarbazones derived from N-(4-hippuric acid)thiosemicarbazide and different carbonyl compounds as antimicrobial agents.

New series of thiosemicarbazone derivatives incorporating a hippuric acid moiety have been synthesized through the reaction of N-(4-hippuric acid)thiosemicarbazide with various carbonyl compounds such as aldehydes, ketones and cyclic ketones. The synthesized compounds were tested against bacterial and fungal strains. Most of compounds, such as 2-(4-(2-(4-fluorobenzylidene)hydrazinecarbothioamido)benzamido)acetic acid showed significant antibacterial and antifungal activities. These compounds comprise a new class of promising broad-spectrum antibacterial and antifungal agents.

Thiourea derivatives incorporating a hippuric acid moiety: synthesis and evaluation of antibacterial and antifungal activities.

New series of thiourea derivatives incorporating a hippuric acid moiety have been synthesized through the reaction of 4-hippuric acid isothiocyanate with various nitrogen nucleophiles such as aliphatic amines, aromatic amines, sulfa drugs, aminopyrazoles, phenylhydrazine and hydrazides. The synthesized compounds were tested against bacterial and fungal strains. Most of compounds, such as 2-(4-(3-(3-bromophenyl)thioureido)benzamido)acetic acid and 2-(4-(3-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)thioureido)benzamido)acetic acid, showed significant antibacterial and antifungal activities. These compounds comprise a new class of promising broad-spectrum antibacterial and antifungal agents.

Synthesis, characterization, and antiviral activity of novel fluorinated isatin derivatives.

ABSTRACT: New series of Schiff's bases, hydrazones, thiosemicarbazones, thiazoles, and thiocarbohydrazones of 5-fluoroisatin were synthesized by the reaction of 5-fluoroisatin with primary amines, hydrazine hydrate, and thiocarbohydrazides. Thiosemicarbazones were prepared by reacting hydrazone derivatives with isothiocyanates. Upon treatment of thiosemicarbazone derivatives with chloroacetone, the thiazole derivatives were obtained. Some of the prepared compounds exhibited antiviral activity.

Synthesis of some azoles incorporating a sulfonamide moiety as anticonvulsant agents.

Many derivatives of heterocyclic compounds containing a sulfonamide thiazole moiety were synthesized through the reaction of 2-(cyano or chloro)-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide with isocyanate followed by halogenated compounds, arylidene, 2-hydroxy benzaldehydes, active methylene compounds, and heterocyclic amines. The anticonvulsant activity for 15 of the synthesized compounds was evaluated and 6 compounds showed protection against picrotoxin-induced convulsion. 4-(6-Amino-3,5-dicyano-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-N-(thiazol-2-yl)benzenesulfonamide (11b) exhibited significant anticonvulsive effects, abolished the tonic extensor phase and offered 100% protection.