Synthesis and biological evaluation of indole-2-carbohydrazides and thiazolidinyl-indole-2-carboxamides as potent tubulin polymerization inhibitors.

A new series of N'-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI50 values < 0.4 µM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.

5-Chloro-N-{4-oxo-2-[4-(trifluoro-meth-yl)phen-yl]-1,3-thia-zolidin-3-yl}-3-phenyl-1H-indole-2-carboxamide.

In the title compound, C(25)H(17)ClF(3)N(3)O(2)S, the five-membered 1,3-thia-zolidine ring adopts a twist conformation. The three F atoms of the CF(3) group are disordered over two sets of sites with refined occupancies of 0.542 (18) and 0.458 (18). In the nine-membered 1H-indoline ring system, the 1H-pyrrole ring forms a dihedral angle of 4.7 (2)° with the benzene ring, while it is twisted at an angle of 46.5 (2)° with respect to the attached phenyl ring. The dihedral angle between the phenyl and trifluoro-methyl-substituted benzene rings is 56.0 (2)°. In the crystal, N-H⋯O hydrogen bonds connect the mol-ecules into a three-dimensional network. In addition, weak C-H⋯O hydrogen bonds and weak C-H⋯π inter-actions are observed.

N-[2-(4-Chloro-phen-yl)-5-methyl-4-oxo-1,3-thia-zolidin-3-yl]pyridine-3-carboxamide.

The title compound, C(16)H(14)ClN(3)O(2)S, crystallizes with two mol-ecules in the asymmetric unit. In the 1,3-thia-zolidine rings, the carbonyl O atoms, the S atoms, the methyl groups and the ring carbon attached to the methyl groups are disordered with occupancy ratios of 0.509 (7):0.491 (7) in one mol-ecule and 0.464 (14):0.536 (14) in the other. The crystal structure is stabilized by inter-molecular N-H⋯N, C-H⋯O hydrogen bonds and C-H⋯Cl inter-actions. In addition, there is a π-π stacking inter-action [centroid-centroid distance = 3.794 (3) Å] between the benzene and pyridine rings.

N-[2-(4-Bromo-phen-yl)-5-methyl-4-oxo-1,3-thia-zolidin-3-yl]pyridine-3-carboxamide.

In the title compound, C(16)H(14)BrN(3)O(2)S, the atoms of the 1,3-thia-zolidine group, except for the N and the C atoms attached to the bromo-benzene ring, are disordered over two sets of sites with occupancies of 0.605 (13) and 0.395 (13). The benzene and pyridine rings make a dihedral angle of 86.2 (2)°. In the crystal, mol-ecules are linked by inter-molecular N-H⋯N and C-H⋯O hydrogen bonds, forming a three-dimensional network. Furthermore, there is a π-π stacking inter-action [centroid-centroid distance = 3.758 (2) Å] between the pyridine and benzene rings.

N-[5-Methyl-2-(2-nitro-phen-yl)-4-oxo-1,3-thia-zolidin-3-yl]pyridine-3-carboxamide monohydrate.

In the title compound, C(16)H(14)N(4)O(4)S·H(2)O, the benzene and pyridine rings make a dihedral angle of 85.8 (1)°. Both enanti-omers of the chiral title compound are statistically disordered over the same position in the unit cell. The methyl and carbonyl group attached to the stereogenic center (C(5) of the thia-zolidine ring) were therefore refined with common site-occupation factors of 0.531 (9) and 0.469 (9), respectively, for each stereoisomer. In the crystal, inter-molecular N-H⋯O, O-H⋯O and O-H⋯N hydrogen bonds link the mol-ecules, forming a three-dimensional supra-molecular network. The crystal structure further shows π-π stacking inter-actions [centroid-centroid distance = 3.5063 (13) Å] between the pyridine rings.

N-[(2S)-2-(4-Bromo-phen-yl)-4-oxo-1,3-thia-zolidin-3-yl]pyridine-3-carboxamide.

In the title compound, C(15)H(12)BrN(3)O(2)S, the dihedral angle between the pyridine and benzene rings is 73.17 (19)°. The five-membered 1,3-thia-zolidine ring has an envelope conformation, with the S atom displaced by 0.196 (1) Šfrom the mean plane of the four other ring atoms. An intra-molecular C-H⋯N inter-action occurs. The crystal structure is stabil-ized by inter-molecular N-H⋯O and C-H⋯O hydrogen bonds and C-H⋯π inter-actions. In addition, a weak π-π stacking inter-action is also observed between the 1,3-thia-zolidine and pyridine rings [centroid-centroid distance = 3.805 (2) Å].

Synthesis, antibacterial and antifungal activities of 3-(1,2,4-triazol-3-yl)-4-thiazolidinones.

A new series of 3-(1,2,4-triazol-3-yl)-4-thiazolidinone derivatives has been synthesized by the reaction of Schiff bases of 3-amino-1,2,4-triazoles with mercaptoacetic acid and 2-mercaptopropionic acid. Their antibacterial and antifungal activities were evaluated against S. aureus, S. epidermidis, C. albicans and C. glabrata.

Synthesis of new triazolyl-N,N-dialkyldithiocarbamates as antifungal agents.

N,N-Dialkylditihiocarbamate derivatives have been well known as broad-range fungicides. In this study, the triazole derivatives of ten new N,N-disubstituted dithiocarbamates (3a-j) were synthesized and their structures were identified by spectral and elemental analysis. Results of the antifungal activity studies showed that some of the compounds tested were active against M. canis, M. gypseum, and T. rubrum at the concentration of 12.5 microg/mL when clotrimazol was used as a standard.

Co-encapsulation of isoniazid and rifampicin in liposomes and characterization of liposomes by derivative spectroscopy.

Taking into consideration the benefits of the combined therapy of isoniazid (INH) and rifampicin (RIF), this study focused on co-encapsulation of INH and RIF in the same liposome formulation. INH was incorporated in the aqueous phase and RIF in the lipid layer. Liposomes containing either INH or RIF were also prepared. All liposome formulations were compared for their loading capacity, encapsulation percentage and release properties. Drug amounts in the liposomes were estimated using peak-to-peak first-order derivative UV spectroscopy. Among the liposome formulations DPPC:chol liposomes showed the highest loading capacity (106.70 +/- 0.12 for INH and 18.17 +/- 0.06 (x 10(-3)) for RIF) and encapsulation percentage (73.84 +/- 0.78 for INH and 81.53 +/- 2.06 for RIF) compared to EPC:chol liposomes (loading capacity 93.36 +/- 0.58 for INH and 17.87 +/- 0.11 (x 10(-3)) for RIF; encapsulation percentage 64.61 +/- 0.51 for INH and 74.45 +/- 0.48 for RIF). Co-encapsulation of INH and RIF increased their individual encapsulation percentage and extended drug release compared to the formulations containing drug alone (Table 2). Results of this study support the conclusion that lipid and water soluble drugs can be successfully co-encapsulated in the same liposome formulation and also show that derivative UV spectroscopy is a sensitive method for direct and accurate quantification of these co-encapsulated drugs.

LC determination of aminoglutethimide enantiomers as dansyl and fluorescamine derivatives in tablet formulations.

Determination of dansyl (AG-DNS) and fluorescamine (AG-F) derivatives of rac-aminoglutethimide in tablet formulation by HPLC has been achieved on a cellulose tris-(3,5-dimethylphenyl carbamate), known as Chiralcel OD and OD-R under normal and reversed phase columns, respectively, using a fluorescence detector (lambda(ex), 360 nm; lambda(em), 530 nm for AG-DNS derivatives; lambda(ex), 395 nm, lambda(em), 495 nm for fluorescamine derivatives (AG-F)). The best results were obtained with mobile phase ethanol:cyclohexane:methanol (95:5:2 v/v/v) for AG-DNS derivatives and acetonitrile:0.5% ortho-phosphoric acid (85:15 v/v) containing 0.26 mM 1-hexanesulfonic acid sodium salt (HSA) for AG-F, respectively. The lower limit of detection (signal to noise ratio of 3:1) were found to be 20 ng ml(-1) for each enantiomer for AG-DNS and 20.5 ng ml(-1) for each diastreoisomer for AG-F.