Benzothiazole Analogs Research Articles

Hybrid pharmacophore design and synthesis of isatin–benzothiazole analogs for their anti-breast cancer activity

A hybrid pharmacophore approach was used to design and synthesize isatin–benzothiazole analogs to examine their anti-breast cancer activity. The cytotoxicity of these compounds were determined using three different human breast tumor cell lines, MDA-MB231, MDA-MB468, MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on all the cancer cell lines examined, the compounds 4-bromo-1-diethylaminomethyl-1 H-indole-2,3-dione ( 2l) and 4-chloro-1-dimethylaminomethyl-3-(6-methyl-benzothiazol-2-ylimino)-1,3-dihydro-indol-2-one ( 5e) emerged as the most active compounds of this series. Importantly, the cytotoxic effect of 2l was 10–15-fold higher on cancer than non-cancer cells, suggesting that this compound can be very effective for the control of breast cancer with low side effects. Since 2l showed effective cytotoxicity on MCF7 cells and arrested the cells at G2/M at a similar concentration, these two phenomena may be closely correlated. We conclude that the isatin-linked benzothiazole analog can serve as a prototype molecule for further development of a new class of anti-breast cancer agents.

Synthesis and Evaluation of Benzothiazole-Based Analogues as Novel, Potent, and Selective Fatty Acid Amide Hydrolase Inhibitors

High-throughput screening (HTS) identified benzothiazole analogue 3 as a potent fatty acid amide hydrolase (FAAH) inhibitor. Structure-activity relationship (SAR) studies indicated that the sulfonyl group, the piperidine ring and benzothiazole were the key components to their activity, with 16j being the most potent analogue in this series. Time-dependent preincubation study of compound 3 was consistent with it being a reversible inhibitor. Activity-based protein-profiling (ABPP) evaluation of 3 in rat tissues revealed that it had exceptional selectivity and no off-target activity with respect to other serine hydrolases. Molecular shape overlay of 3 with a known FAAH inhibitor indicated that these compounds might act as transition-state analogues, forming putative hydrogen bonds with catalytic residues and mimicking the charge distribution of the tetrahedral transition state. The modeling study also indicated that hydrophobic interactions of the benzothiazole ring with the enzyme contributed to its extraordinary potency. These compounds may provide useful tools for the study of FAAH and the endocannabinoid system.

Microwave‐assisted “green” synthesis of 2‐alkyl/arylbenzothiazoles in one pot: A facile approach to anti‐tumor drugs

Abstractmagnified imageA series of new 2‐alkyl/arylbenzothiazoles has been synthesized on the basis of the potent and selective in vitro anti‐tumor properties of 2‐(3,4‐diethoxyphenyl)‐5‐fluorobenzothiazole. The synthesis of benzothiazole analogs was achieved via microwave irradiation of a 1:1 mixture of o‐aminothiophenol and alkyl/aryl acylacetonitriles at temperature of 200°C for 10 min. The yields are very good to excellent. All the products were characterized by 1H nmr, 13C nmr and elemental analysis.

Anti-tumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces single-strand breaks and DNA-protein cross-links in sensitive MCF-7 breast cancer cells

The fluorinated benzothiazole analogue 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) exhibits selective and potent anticancer activity, and its lysylamide prodrug (Phortress, NSC 710305) recently entered Phase I clinical trials in the United Kingdom. Only cancer cells sensitive to the anti-proliferative effects of 5F 203 deplete this drug candidate from nutrient media. 5F 203 induces cell cycle arrest, cytochrome P450 1A1 (CYP 1A1) mRNA and protein expression, and is metabolized into reactive electrophilic species that can covalently bind to DNA and form adducts in sensitive (i.e., MCF-7) but not in resistant (i.e., MDA-MB-435) breast cancer cells. In this present study, we investigated additional anticancer effects of 5F 203 in MCF-7 cells. In addition, we sought to determine if cells deficient in the xeroderma pigmentosum D gene, a gene critical in DNA repair, would show greater sensitivity to the cytotoxic effects of 5F 203 than those complemented with XPD. Alkaline Elution revealed that 5F 203 induced single-strand breaks and DNA-protein cross-links in sensitive MCF-7 cells. In contrast, we detected no double-strand breaks or protein-associated strand breaks typically associated with topoisomerase I (top1) or topoisomerase II (top2) inhibition. In addition, 5F 203 was unable to trap top1- or top2-DNA cleavage complexes in MCF-7 cells. 5F 203 induced cell cycle arrest in MCF-7 cells following DNA damage after brief exposures. Cells deficient in the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene displayed sensitivity to 5F 203 while cells complemented with XPD displayed resistance to 5F 203. These data suggest that the anti-cancer activity of 5F 203 depends upon targets other than top1 or top2 and on the ability of this benzothiazole to form single-strand breaks and DNA-protein cross-links in cancer cells.

DNA damage and cell cycle arrest induced by 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is attenuated in aryl hydrocarbon receptor deficient MCF-7 cells.

The fluorinated benzothiazole analogue 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is a novel agent with potent and selective antitumour properties and, in the form of its L-lysylamide prodrug Phortress (NSC 710305), is a current candidate for early phase clinical studies. Previous findings have indicated that cytochrome P450 1A1 (CYP1A1) may play a role in the antitumour activity of molecules in the benzothiazole series including the nonfluorinated parent compound 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) (Kashiyama et al, 1999; Chua et al, 2000; Loaiza-Pérez et al, 2002). In this study, we assessed and verified that a fully functional aryl hydrocarbon receptor (AhR) signalling pathway is a necessary requisite for the induction of efficient cytotoxicity by 5F 203 in MCF-7 wild-type sensitive cells. Drug exposure caused MCF-7 sensitive cells to arrest in G1 and S phase, and induced DNA adduct formation, in contrast to AhR-deficient AHR100 variant MCF-7 cells. In sensitive MCF-7 cells, induction of CYP1A1 and CYP1B1 transcription (measured by luciferase reporter assay and real-time reverse transcriptase-polymerase chain reaction (RT–PCR)), and 7-ethoxyresorufin-O-deethylase (EROD) activity was demonstrated, following treatment with 5F 203. In contrast, in resistant AHR100 cells, drug treatment did not affect CYP1A1 and CYP1B1 transcription and EROD activity. Furthermore, AHR100 cells failed to produce either protein/DNA complexes on the xenobiotic responsive element (XRE) sequence of CYP1A1 promoter (measured by electrophoretic mobility shift assay) or DNA adducts. The data confirm that activation of the AhR signalling pathway is an important feature of the antitumour activity of 5F 203.

Protonation Dependent Photoinduced Intramolecular Charge Transfer in 2‐(p‐Dimethylaminostyryl)Benzazoles

The absorption and fluorescence spectra of 2‐(p‐dimethylaminostyryl)benzoxazole, DMASBO, and its benzothiazole analogue, DMASBT, have been studied in different solvents and at various acid concentrations. Two types of monocation are formed simultaneously in all solvents at relatively lower acid concentrations. The neutral DMASBO and DMASBT as well as the monocations formed by protonation of the –N = atom exhibit highly solvatochromic intramolecular charge transfer (ICT) emission. This indicated an increase in the dipole moment of the S1 state (μe). The μe values, which were calculated from the solvatochromic shifts and the ground state dipole moments, came out to be 14.3 and 12.6 D for DMASBT and DMASBO, respectively. For their azolium cations μe are 9.0 and 8.6 D. on the other hand, the monocations formed by protonation of the –NMe2 group as well as the dications formed at relatively higher acid concentration, showed insignificant spectral shift on changing the solvent polarity. Also, the effect of the heteroatom and the protonation site on the ICT process is discussed.

Antitumour benzothiazoles. Part 20: 3′-Cyano and 3′-Alkynyl-Substituted 2-(4′-Aminophenyl)benzothiazoles as new potent and selective analogues

The synthesis of a new series of antitumour 2-(4-aminophenyl)benzothiazole analogues, substituted in the 3′-position by cyano or alkynyl groups, is described. Several of the analogues, notably the 5-fluorinated compounds 7c and 9c, were found to possess potent in vitro activity against MCF-7 and MDA 468 human cancer cell lines. More comprehensive in vitro analysis (NCI 60-cell line) established compound 7c as a particularly potent and selective 2-(4-aminophenyl)benzothiazole analogue.

Application of 2-(3,5,6-Trifluoro-2-hydroxy-4-methoxyphenyl)benzoxazole and -benzothiazole to Fluorescent Probes Sensing pH and Metal Cations

2-(3,5,6-Trifluoro-2-hydroxy-4-methoxyphenyl)benzoxazole (3) and benzothiazole analogue (4) are prepared by the two-step procedures from the corresponding 2-(pentafluorophenyl)benzazoles. Benzoxazole 3 is applicable to a fluorescent probe sensing magnesium cation, and 4 is suitable for sensing zinc cation. Both fluorophores 3 and 4 are sensitive to the pH change at pH 7-8, resulting in large fluorescence enhancement under basic conditions. Their high sensitivity to pH and selectivity in metal cations are ascribed to the high acidity of the fluorophenol moiety.

Formation of reissert analogs from benzimidazole and use of carboxylic acids in a retro‐reissert reactionReissert Analogs from Benzimidazole

AbstractReissert analogs have been formed in high yields from benzimidazole using trimethylsilyl cyanide and chloroformates. A retro‐Reissert reaction can be effected on the products, their carbon‐2 alkylated derivatives and benzothiazole analogs, by treatment with hexanoic or benzoic acids.

Rubber Chemicals from Cyclic Amines. VI. 2-(4-Morpholinodithio)Benzothiazole and Related Compounds as Curing Agents

Abstract Unlike the case of the thiazolesulfenamides, the electronic effect of substitution in the thiazole moiety on the curing properties of these compounds is not consistent. The unsubstituted 2-(4-morpholinodithio)benzothiazole 1 is superior to the 6-ethoxy, 5-chloro, or 6-nitro substituted derivatives in curing properties. The 5-ethoxycarbonyl-2-(morpholinodithio)-4-methylthiazole is comparable to 1 in scorch delay and curing activities. It is superior to the 5-acetyl and the unsubstituted 4-methyl thiazole derivatives. Both the benzoxazole and benzimidazole derivatives are inferior to the benzothiazole and 4-methyl thiazole analogs.

The European Corn Borer, Pyrausta Nubilalis (Hubn.), and Its Principal Host Plant VII. Larval Feeding Behavior and Host Plant Resistance1

Host-plant resistance to the European corn borer is manifested as increased larval mortality, inhibition of larval growth, and reduction in larval feeding. Leaf lesions caused by larval feeding are smaller and fewer per infesting borer on resistant lines than on susceptible lines of corn. Resistance factor A (6-methoxybenzoxazolinone) exerted a deleterious effect on feeding of firstinstar larvae, acting as a feeding deterrent and not as a simple repellent. Reducation in duration of larval feeding was proportional to RFA concentration, but inhibition of larval growth by RFA could not be accounted for on this basis. No significant correlation between feeding suppression and growth inhibition was found in experiments using a series of 15 benzoxazolinone and benzothiazole analogs. Lowering of RFA inhibitory action by high concentration of dietary sugar was not caused by a masking of RFA effects on feeding behavior. The available evidence indicates that RFA inhibited larval growth by metabolic action, not via behavioral effects. Under field conditions, larval mortality on borer-resistant plants was higher than that observed in the laboratory among larvae on purified diets containing comparable concentrations of RFA. The reduced feeding and inhbiited growth induced by RFA probably tends to increase larval mortality through prolonging the exposure of the weakened larvae to adverse environmental conditions.

Benzothiazoles. VII

1) Possible routes of preparing benzothiazole analogs of chloramphenicol were examined, one of which was proved to be promising. The route is as follows: 2-Ethyl-, 2-ethyl-6-nitro-, 2-dichloroethyl-6-nitro-, 2-acetyl-6-nitro-(X), and to 2-α-bromoacetyl-6-nitrobenzothiazole. Overall yield of (X) by the present route was found to be 18%.2) During the present investigation, following new compounds were prepared: Benzothiazolyl-2-carbohydrazide, m.p. 171°; 2-acetylbenzothiazole, m.p. 107-108°, its semicarbazone, m.p. 258° (decomp.); 2-acetyl-6-nitrobenzothiazole, m.p. 191-192°; 2-α, α′-dichloro-6-nitrobenzothiazole, m.p. 93-94°; 2-bromoacetyl-6-nitrobenzothiazole, m.p. 146-147°.