First Synthesis for Bis-Spirothiazolidine Derivatives as a Novel Heterocyclic Framework and Their Biological Activity.

BACKGROUND: Spirothiazolidines are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity. OBJECTIVE: To report the first synthesis of Bis Spiro-thiazolidine as a novel heterocyclic ring system. METHODS: One-pot three-component reaction including condensation of p-phenyllene diamine; cyclohexanone and thioglycolic acid produced Spiro-thiazolidine 4, which underwent further condensation with cyclohexanone and thioglycolic acid with equimolar ratio to introduce Bis-Spiothiazolidine 5 as the first synthesis. Also, bis spiro-thiazolidine arylidene derivatives 6-13 were synthesized by the reaction of Bis-Spiothiazolidine 5 with different aromatic benzaldehydes. RESULTS: Four compounds 13, 12, 9 and 11 have shown highly significant anticancer activity compared to Doxorubicin® (positive control) against Human liver carcinoma (HepG2) and Human Normal Retina pigmented epithelium (RPE-1) cell lines. CONCLUSION: The novel bis-spirothiazolidine deriviatives have been synthesized for the first time and showed excellent anticancer activities compare with the corresponding spirothiazolidine derivatives.

Development of a Novel Series of Anticancer and Antidiabetic: Spirothiazolidines Analogs.

4-(4-Aminophenyl)-1-thia-4-azaspiro[4.5]decan-3-one 1 was prepared and allowed to react with nitrogen nucleophiles to give the corresponding hydrazones 2-4. Further, compound 1 underwent diazotization and afforded the parallel hydrazono derivative 5; moreover, compound 1 refluxed with active methylene derivatives yielded the corresponding aminospirothiazolo pyridine-carbonitrile derivative 6 and spirothiazolopyridinone-carbonitrile derivative 7. Condensation of spirothiazolidine 1 with 4-chlorobenzaldehyde gave the corresponding spiro arylidiene derivative 8, which was utilized as a component of Micheal addition to react with excess of nitrogen nucleophiles to yield novel ring frameworks 4-(3'-(4-chlorophenyl)-spiro [cyclohexane-1,5'-pyrazolo[3,4-d]thiazol]-6'(1'H)-yl)aniline (9) and 4-(3'-(4-chlorophenyl)-6'H- spiro[cyclohexane-1,5'-thiazolo[5,4-d]isoxazol]-6'-yl)aniline (10). Finally, when spirothiazolo pyridinone-carbonitrile derivative 7 sodium salt generated in situ was reacted with different alkyl halides, it produced the corresponding N-derivatives 12-16. Three compounds, 6, 14, and 16, showed high significantly anticancer activities compared with Doxorubicin® (positive control) against human breast carcinoma (MCF-7) and human liver carcinoma (HepG-2) cell lines. On the other hand, compounds 6 and 9 showed higher therapeutic indices for both of alpha-amylase inhibitor and alpha-glucosidase inhibitor than the other tested compounds compared with the antidiabetic Acarbose (positive control).

Synthesis, Molecular Docking and in Vitro Screening of Some Newly Synthesized Triazolopyridine, Pyridotriazine and Pyridine⁻Pyrazole Hybrid Derivatives.

A series of novel pyridine and fused pyridine derivatives have been prepared starting from 6-(3,4-dimethylphenyl)-2-hydrazinyl-4-(thiophen-2-yl)-pyridine-3-carbonitrile 1 which on treatment with appropriate formic acid, acetic acid/ acetic anhydride, benzoyl chloride and/or carbon disulfide afforded the corresponding triazolopyridine derivatives 2⁻5. Also, treatment of hydrazide 1 with diethyloxalate, chloroacetyl chloride, chloroacetic acid and/or 1,2-dichloroethane yielded the corresponding pyridotriazine derivatives 7⁻10. Further transformation of compound 1 with a different active methylene group, namely acetyl acetone, diethylmalonate, ethyl cyanoacetate, ethyl benzoylacetate and/or ethyl acetoacetate, produced the pyridine⁻pyrazole hybrid derivatives 11⁻15. These newly synthesized compounds (1⁻15) were subjected to in silico molecular docking screenings towards GlcN-6-P synthase as the target protein. The results revealed moderate to good binding energies of the ligands on the target protein. All the newly prepared products exhibited antimicrobial and antioxidant activity.

Synthesis of Some New Pyridazine Derivatives for Anti-HAV Evaluation.

4-(2-(4-Halophenyl)hydrazinyl)-6-phenylpyridazin-3(2H)-ones 1a,b were prepared and treated with phosphorus oxychloride, phosphorus pentasulphide and ethyl chloroformate to give the corresponding chloropyridazine, pyridazinethione, oxazolopyridazine derivatives 2-4, respectively. Compound 2 reacted with hydrazine hydrate to afford hydrazinylpyridazine 7. The reaction of 4-(2-(4-chlorophenyl)hydrazinyl)-3-hydrazinyl-6-phenylpyridazine (7) with acetic anhydride, p-chlorobenzaldehyde and carbon disulphide gave the corresponding pyridazinotriazine derivatives 8-10. On the other hand, 5-(4-chlorophenylamino)-7-(3,5-dimethoxybenzylidene)-3-phenyl-5H-pyridazino[3,4-b][1,4]thiazin-6(7H)-one (11) was prepared directly from the reaction of compound 3 with chloroacetic acid in presence of p-chlorobenzaldehyde. Compound 11 reacted with nitrogen nucleophiles (hydroxylamine hydrochloride, hydrazine hydrate) and active methylene group-containing reagents (malononitrile, ethyl cyanoacetate) to afford the corresponding fused compounds 12-15, respectively. Pharmacological screening for antiviral activity against hepatitis A virus (HAV) was performed for the new compounds. 4-(4-Chlorophenylamino)-6-phenyl-1,2-dihydropyridazino[4,3-e][1,2,4]triazine-3(4H)-thione (10) showed the highest effect against HAV.

Synthesis and Anticancer Activity of New 1-Thia-4-azaspiro[4.5]decane, Their Derived Thiazolopyrimidine and 1,3,4-Thiadiazole Thioglycosides.

New 1-thia-azaspiro[4.5]decane derivatives, their derived thiazolopyrimidine and 1,3,4-thiadiazole compounds were synthesized. The thioglycoside derivatives of the synthesized (1,3,4-thiadiazolyl)thiaazaspiro[4.5]decane and thiazolopyrimidinethione compounds were synthesized by glycosylation reactions using acetylated glycosyl bromides. The anticancer activity of synthesized compounds was studied against the cell culture of HepG-2 (human liver hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma) and HCT116 (human colorectal carcinoma) cell lines and a number of compounds showed moderate to high inhibition activities.

Synthesis and pharmacological activities of some new triazolo- and tetrazolopyrimidine derivatives.

A new series of fused triazolo- and tetrazolopyrimidine derivatives 2-14 were synthesized and their anti-inflammatory and ulcerogenic activities were evaluated. The pharmacological screening showed that many of these obtained compounds have good anti-inflammatory activities, comparable to the reference drug. The toxicity of the compounds was also assayed via the determination of their LD50 values. The structures of newly synthesized compounds were confirmed by IR, 1H-NMR, MS spectral data and elemental analysis.

Synthesis of new macrocyclic polyamides as antimicrobial agent candidates.

A series of macrocyclic imides and Schiff-bases have been prepared via the cyclocondensation of pyridine-2,6-dicarbonyl dichloride (1) with L-ornithine methyl ester to give the corresponding macrocyclic bisester 2. Treatment of 2 with hydrazine hydrate gave macrocyclic bisacid hydrazide 3, which was used as starting material. Condensation of bishydrazide 3 with diacid anhydrides or aromatic aldehydes in refluxing acetic acid or ethanol gave the corresponding macrocyclic bisimides 4, 5a,b and macrocyclic bis- hydrazones 6a-j, respectively. The structure assignments of the new compounds were based on chemical and spectroscopic evidence. The antimicrobial screening showed that many of these newly synthesized compounds have good antimicrobial activities, comparable to ampicillin and ketaconazole used as reference drugs.

Heterocyclic compounds based on 3-(4-bromophenyl) azo-5-phenyl-2(3H)-furanone: anti-avian influenza virus (H5N1) activity.

1 3-[2-(4-Bromphenyl)hydrazono]-5-phenyl-furan-2(3H)-one () was used for preparation of some novel pyrazole, pyridazinone, oxadiazole, triazole, thiazolidine and thioxopyrimidine derivatives. Some of the prepared products were tested for anti-avian influenza virus activity and revealed promising antiviral activity against H5N1 virus [A/Chicken/Egypt/1/20 % (H5N1)] by determination of both EC50 and LD50 and confirmed by plaque reduction assay on Madin-Darby canine kidney cells. Compounds 3-[2-(4-bromophenyl)hydrazono]-5-phenylfuran-2(3H)-one (1), 1-(4-bromophenyl)-N-hydroxy-5-phenyl-1H-pyrazole-3-carboxamide (5) and 1-(4-bromophenyl)-N-{2,3-dihydro-4-hydroxy-3-phenyl-6-oxo-2-thioxopyrimidin-1(6H)-yl}-5-phenyl-1H-pyrazole-3-carboxamide (12a) showed the highest effects. Detailed synthesis, spectroscopic data, and antiviral activity of the synthesized compounds are reported.

Anti-HSV-1 activity and mechanism of action of some new synthesized substituted pyrimidine, thiopyrimidine and thiazolopyrimidine derivatives.

A series of heterocyclic derivatives 2-16 conjugated with tetrahydronaphthalene moiety were synthesized as antiviral agents by using 1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone as starting material. The antiviral screening showed that many of these obtained compounds have good antiviral activities comparable to Acyclovir as reference control. Two compounds 13 and 15 gave over 90% inhibition and considered to be highly promising and on confirming their activity and comparing them to antiviral activity of Acyclovir. The detailed synthesis, spectroscopic data, and antiviral screening for synthesized compounds were reported.