Benzothiophenes as Potent Analgesics Against Neuropathic Pain.

Neuropathic pain arises because of neuronal injury. Unlike inflammatory pain which can be managed by classical nonsteroid anti-inflammatory drugs (NSAIDs), neuropathic pain is difficult to treat. The classical NSAIDs work through inhibition of cyclooxygenase 2 (COX2) enzyme. However, COX2 inhibitors are insufficient to treat neuropathic pain. Hence, it becomes important to explore for novel molecules acting through cell surface molecules like ion channels, for the treatment of neuropathic pain. We investigated multiple bromobenzothiophene carboxamides for their efficacy against neuropathic pain. Interestingly, AS6 was found to be very effective in treating neuropathic pain through inhibition of Kv4.3 ion channel. AS6 also reduced the COX2 overexpression associated with neuropathic pain. These results as well as results from our previous study indicate that AS6 can be a potent antinociceptive agent against both inflammatory and neuropathic pain.

Stable and potent analogues derived from the modification of the dicarbonyl moiety of curcumin.

Curcumin has shown promising therapeutic utilities for many diseases, including cancer; however, its clinical application is severely limited because of its poor stability under physiological conditions. Here we find that curcumin also loses its activity instantaneously in a reducing environment. Curcumin can exist in solution as a tautomeric mixture of keto and enol forms, and the enol form was found to be responsible for the rapid degradation of the compound. To increase the stability of curcumin, several analogues were synthesized in which the diketone moiety of curcumin was replaced by isoxazole (compound 2) and pyrazole (compound 3) groups. Isoxazole and pyrazole curcumins were found to be extremely stable at physiological pH, in addition to reducing atmosphere, and they can kill cancer cells under serum-depleted condition. Using molecular modeling, we found that both compounds 2 and 3 could dock to the same site of tubulin as the parent molecule, curcumin. Interestingly, compounds 2 and 3 also show better free radical scavenging activity than curcumin. Altogether, these results strongly suggest that compounds 2 and 3 could be good replacements for curcumin in future drug development.

Benzothiophene carboxamide derivatives as inhibitors of Plasmodium falciparum enoyl-ACP reductase.

Benzothiophene derivatives like benzothiophene sulphonamides, biphenyls, or carboxyls have been synthesized and have found wide pharmacological usage. Here we report, bromo-benzothiophene carboxamide derivatives as potent, slow tight binding inhibitors of Plasmodium enoyl-acyl carrier protein (ACP) reductase (PfENR). 3-Bromo-N-(4-fluorobenzyl)-benzo[b]thiophene-2-carboxamide (compound 6) is the most potent inhibitor with an IC50 of 115 nM for purified PfENR. The inhibition constant (Ki) of compound 6 was 18 nM with respect to the cofactor and 91 nM with respect to crotonoyl-CoA. These inhibitors showed competitive kinetics with cofactor and uncompetitive kinetics with the substrate. Thus, these compounds hold promise for the development of potent antimalarials.

Telomerase targeted anticancer bioactive prodrug by antisense-based approach.

A deoxy 11-mer oligonucleotide 5'-GTTAGGGTTAG-3', complementary to a repeat sequence of human telomerase RNA template has been linked through phosphate and a C-2 linker to a bioactive tetraglycine conjugate of curcumin, a well-known antitumor herbal spice component of turmeric. This molecule has been transfected into KB and HeLa cell lines and found to affect cell growth in the former. This DNA-curcumin-tetraglycine acts as a prodrug being targeted by antisense mechanism to telomerase.

Curcumin recognizes a unique binding site of tubulin.

Although curcumin is known for its anticarcinogenic properties, the exact mechanism of its action or the identity of the target receptor is not completely understood. Studies on a series of curcumin analogues, synthesized to investigate their tubulin binding affinities and tubulin self-assembly inhibition, showed that: (i) curcumin acts as a bifunctional ligand, (ii) analogues with substitution at the diketone and acetylation of the terminal phenolic groups of curcumin are less effective, (iii) a benzylidiene derivative, compound 7, is more effective than curcumin in inhibiting tubulin self-assembly. Cell-based studies also showed compound 7 to be more effective than curcumin. Using fluorescence spectroscopy we show that curcumin binds tubulin 32 Å away from the colchicine-binding site. Docking studies also suggests that the curcumin-binding site to be close to the vinblastine-binding site. Structure-activity studies suggest that the tridented nature of compound 7 is responsible for its higher affinity for tubulin compared to curcumin.