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, molecular docking and biological activity evaluation of some novel indole derivatives as potent anticancer active agents and apoptosis inducers.

Reaction of 5-morphilinosulfonylisatin (1) with acetophenones (2a-e) afforded 3-hydroxy-3-substituted-2-oxoindoles 3a-e, when treated with acetic acid the expected 3-phenacylidene-2-oxoindoles 4a-d and 4-hydroxy-5'-(morpholinosulfonyl) spiro [chromene-2, 3'-indolin]-2'-one 6 were obtained. Isatin derivative (1) was stirred with cyano derivatives to produce the arylidines (7a-c), while under reflux condition, it gave pyrrolo[2,3-b]indoles (8, 9). Moreover, istain (1) reacted with pyrazolo-5-one or 3-substituted phenol in presence of malononitrile to afford spiroxindole derivatives (10a,b) and (11a,b). Also, compounds (10a,b) and (11a,b) were obtained through cyclization of (7a) with pyrazolo-5-one or 3-substituted phenol. The obtained compounds were identified by IR, 1H NMR, 13C NMR and elemental analysis. Anticancer activity against three cancer cell lines (HepG-2, HCT-116 and MCF-7) were evaluated using sulforhodamine B assay method. Compounds 4b, 4c, 7a, 7c and 9 showed broad spectrum anticancer activity on the three tested cell lines with IC50 values less than 10 µM. Cell cycle analysis was performed for the most promising derivatives, compounds 4b and 7c arrested HepG-2 cells at G2-M phase, while compounds 7a and 9 accumulated cells at G0-G1 phase, all of them induced apoptosis at priG1 phase in the range of (11.32-19.17%). Additionally compounds 4b, 7a and 9 showed more potent activity against EGFR than Lapatinib, their IC50 values are from 0.019 to 0.026 µM while IC50 of Lapatinib is 0.028 µM. Molecular docking studies were conducted to investigate the binding mode, amino acid interactions and free binding energy of these potent derivatives.

Synthesis and biological evaluation of bis-imidazolidineiminothiones: a comparative study.

A series of 15 novel symmetrical and non-symmetrical bis-imidazolidineiminothiones (6a-g, 7a-e, 8a,b, and 9) with various substituents at N-(1) (p-tolyl, p-methoxyphenyl, p-ethoxyphenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, and 3,5-dichlorophenyl) and different linkers between the N-(3) atoms [4,4'-oxybis(4,1-phenylene), 2,2'-dimethoxybiphenyl, and (1,3,3-trimethylcyclohexyl)methyl)] were prepared in 65-75% yields from substituted N-arylcyanothioformanilides and various bis-isocyanates. Screening for cytotoxicity against the HEPG2, HEP2, MCF7, and HCT116 tumor cell lines gave IC50 values ranging from 6.3 to 84.6 µM, where compounds 6b,d,e,g and 7a were markedly active against a least one cell line, underlining the matching effect of properly positioned substituents on N-(1) and the appropriate N-(3)-N-(3) linker. Likewise, all heterocyles were tested against microbial organisms (Pseudomonas aeruginosa, Sarcina lutea, Bacillus pumilus, and Micrococcus luteus) and fungal strains (Candida albicans and Penicilium chrysogenum). Most compounds showed significant antibacterial and antifungal activities, reaching in certain cases the same level of antimicrobial activity as the standard antibacterial agent erythromycin and the antifungal agent metronidazole. The antimicrobial activity was further supported by quantitative assessment of susceptibilities of a selection of the preceding microorganisms using minimum inhibitory concentration and minimum bactericidal concentration techniques. Finally, the antiviral properties of all compounds were investigated against the viral strains HAV, HSV1, and CoxB4, where 6c,d,f and 7a,c,e were markedly active against one or two viral strains, reducing the virus plaque count of various viral strains by 66 to 88%. Structure activity relationship studies revealed several matching pairs of aromatic substituents on N-(1) and the N-(3)-N-(3) linkers, which could serve to optimize structural features for high activity to eventually render such compounds clinically useful drug agents.

Synthesis and characterization of new types of halogenated and alkylated imidazolidineiminothiones and a comparative study of their antitumor, antibacterial, and antifungal activities.

A series of twenty novel imidazolidineiminothiones (4-8) with various substituents at N-(1) and N-(3) were synthesized by various permutations of halogenated and alkylated N-arylcyanothioformanilides (1) with aromatic isocyanates (2). Preliminary screening of all compounds against Ehrlich ascites carcinoma cells (EAC) indicated that 5d, and 8a-c were the most active compounds as they displayed the highest percent inhibition of cell viability (80%, 70%, 80%, and 70%, respectively). Thus, they were further subjected to in vitro biological evaluation against other tumor cancer cell lines (HEPG2, HEP2, MCF7, HELA, and HCT116). The IC50 values ranged from 3.12 to 12.1 µg/mL where compound 8b (N-(1): 2,4-dimethoxyphenyl; N-(3): 4-methoxyphenyl) was markedly active against all cell lines and consistently produced low IC50 values in all cases (ranging from 3.12 to 4.34 µg/mL). This underscored the synergistic effect of the suitably positioned methoxy groups on the aromatic rings of N-(1) and N-(3) of the imidazolidineiminothiones. All compounds were also tested against microbial organisms (Escherichia coli, Sarcina lutea, Bacillus subtilis, and Staphylococcus aureus), and fungal strains (Candida albicans and Aspergillus flavus). Most tested compounds showed significant activities which could be optimized with the appropriate selection of matching aromatic substituents on N-(1) and N-(3).

Synthesis, characterization and derivatization of some novel types of mono- and bis-imidazolidineiminothiones and imidazolidineiminodithiones with antitumor, antiviral, antibacterial and antifungal activities--part I.

Halogenated and alkylated N-arylcyanothioformanilides were reacted with the nucleophilic reagents triethylamine, hydrazine and diphenyldiazomethane to produce N-arylcyanothioformanilide ammonium salts, a thiosemicarbazide and a 2-(arylamino)-3,3-diphenylacrylonitrile, respectively. They also underwent several types of electrophilic reactions with aryl-, arylbisisocyanates and arylisothiocyanates to yield mono- and bis-imidazolidineiminothiones and imidazolidineiminodithiones. Treatment of imidazolidineiminothiones with hydrogen sulfide, substituted ortho-phenylenediamines and thiocarbohydrazide afforded the corresponding thiohydantoin, quinoxaline and imidazotriazine derivatives. Several of the synthesized products were subjected to in vitro biological evaluation against antitumor, antiviral, antimicrobial and antifungal strains. Most tested compounds showed significant activities.