Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones.

Cyclization of substituted thiosemicarbazones with α-bromo-4-cyanoacetophenone allows rapid single-step sustainable syntheses of 4-cyanophenyl-2-hydrazinylthiazoles libraries (30 examples, 66-79%). All show anticancer efficacy against HCT-116 and MCF-7 carcinoma cell lines with the majority being more active than cisplatin positive controls. The compounds 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f) and 2-(2-((pentafluorophenyl)methylene)-hydrazinyl)-4-(4-cyanophenyl)thiazole (3a') show optimal GI50 values (1.0 ± 0.1 µM and 1.7 ± 0.3 µM) against MCF-7 breast cancer cells. Against colorectal carcinoma HCT-116 cells, (2-(2-(3-bromothiophen-2-yl)methylene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3b'), 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f), 2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3n) and 2-(2-(1-(4-fluorophenyl)ethylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3w) are the most active (GI50 values: 1.6 ± 0.2, 1.6 ± 0.1, 1.1 ± 0.5 and 1.5 ± 0.8 µM respectively). Control studies with MRC-5 cells indicate appreciable selectivity towards the cancer cells targeted. Significant (p < 0.005) growth inhibition and cytotoxicity effects for the thiazoles 3 were corroborated by cell count and clonogenic assays using the same cancer cell lines at 5 and 10 µM agent concentrations. Cell cycle, caspase activation and Western blot assays demonstrated that compounds 3b' and 3f induce cancer cell death via caspase-dependent apoptosis. The combination of straight forward synthesis and high activity makes the thiazoles 3 an interesting lead for further development.

Synthesis and in Silico Docking Studies of Ethyl 2-(2-Arylidene-1-alkylhydrazinyl)thiazole-4-carboxylates as Antiglycating Agents.

Ethyl 2-(2-arylidene-1-alkylhydrazinyl)thiazole-4-carboxylates (1a-k) were synthesized by alkylation on HN- of ethyl 2-(2-arylidenehydrazinyl)thiazole-4-carboxylates. The proposed structures (1a-k) are corroborated by spectro-analytical techniques like UV, FT-IR, 1 H-, 13 C-NMR and HR-MS. All synthesized compounds were screened for their antiglycation and antioxidant assays. The in vitro antiglycation results revealed promising activity of compounds 1a, 1b, 1d, 1e, 1f, 1g, 1j and 1k with IC50 values 0.0004±1.097-17.22±0.538 µM when compared to standard, aminoguanidine (IC50 =25.50±0.337 µM). Among all tested compounds 1j and 1k are the best antiglycating agents with IC50 values 1.848±0.646 and 0.0004±1.097 µM, respectively. The in-silico studies also agree with these results where binding energy for 1j and 1k was found to be -9.25 and -8.42 kcal/mol with calculated dissociation constants of 0.16 and 0.67 µM, respectively. The antiglycation results demonstrate the application of these compounds in reducing diabetic complications.

Synthesis, QSAR and anti-HIV activity of new 5-benzylthio-1,3,4-oxadiazoles derived from α-amino acids.

2-(1-[(4-Chloro/methylphenylsulfonylamino)alkyl]-5-thioxo-4,5-dihydro-1,3,4-oxadiazoles (4a-e) were synthesized, in four steps, via the sulfonyl derivatives of l-amino acids (l-alanine, l-methionine and l-phenylalanine) 1a-e, the esters 2a-e, the hydrazides 3a-e and finally the cyclization to 4a-e. Alkylation of 4a-e with 1.0 mole eq. of substituted benzyl halides furnished S-benzyl derivatives 5a-t, while 1.1 mole eq. yielded major 5a-t and minor amount of 6a-d. Alternatively, treatment of 4a-e with 2.0 mole eq. of substituted benzyl halides furnished 6a-d only. The structures of 5b and 5l were further confirmed by single crystal X-ray analysis. Compounds 5a-t and 6a-d showed no selective inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 5f and 5j-5q exhibited some inhibitory activity against both types with EC(50) values (>11.50 - >13.00 µg/mL). These results suggest that the structural modifications of these compounds might lead to the development of new antiviral agents. The quantum structure-activity relationship of these novel structural congeners is discussed.

4-Methyl-benzene-carbothio-amide.

In the title mol-ecule, C(8)H(9)NS, the mean plane of the carbothio-amide group is twisted slightly with respect to the mean plane of the benzene ring, making a dihedral angle of 17.03 (10)°. The crystal structure is stabilized by inter-molecular N-H⋯S hydrogen bonds, resulting in the formation of eight-membered rings lying about inversion centers and representing R(2) (2)(8) and R(4) (2)(8) motifs. Futhermore, these hydrogen bonds build up chains parallel to the b axis.

4-Methoxy-benzene-carbothio-amide.

The asymmetric unit of the title compound, C(8)H(9)NOS, contains two independent mol-ecules with the meth-oxy groups oriented in opposite conformations. The mean planes of the carbothio-amide groups are tilted by 7.88 (15) and 11.16 (9)° from the mean planes of the benzene rings. In the crystal, the mol-ecules form dimers via intermolecular N-H⋯S inter-molecular hydrogen bonds, resulting in eight-membered rings of R(2) (2)(8) graph-set motif. The dimers are further linked by C-H⋯O hydrogen bonds into chains along the c axis. Adjacent chains inter-act through inter-molecular N-H⋯S hydrogen bonds, generating eight-membered rings of R(4) (2)(8) graph-set motif.

In vitro antitumor and antiviral activities of new benzothiazole and 1,3,4-oxadiazole-2-thione derivatives.

A series of new benzothiazole derivatives 6a-h have been synthesized, in five steps, from substituted phenols via the 1,3,4-oxadiazole-2-thiones 5a-h. The in vitro antitumor activity of the compounds obtained was investigated and the benzothiazol derivatives 6d and 6e showed strong effects on leukaemia cell lines CCRF-CEM (CC50=12+/-2 micromol L(-1), 8+/-1 micromol L(-1), respectively). These compounds are leading candidates for further development. The title compounds were tested against representatives of several virus families containing single stranded RNA genomes, either positive-sense (ssRNA+), or negativesense (RNA-), and against double-stranded RNA genomes (dsRNA), as well as some Flaviviridae viruses.

Unusual synthesis of carbohydrate sec-sec ether-linked pseudodisaccharides.

In this paper, we describe the synthesis of sec-sec ether-linked pseudodisaccharides by the coupling of various secondary carbohydrate alcohols with di-O-isopropylidene allose 3-O-triflate. Reactions proceeded with inversion of configuration to give the 3-substituted di-O-isopropylidene glucose derivatives. The crystal structure of a sec-sec ether-linked pseudodisaccharide is reported.