An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities

Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches

New antimicrobials based on the adarotene scaffold with activity against multi-drug resistant staphylococcus aureus and vancomycin-resistant enterococcus

The global increase in infections by multi-drug resistant (MDR) pathogens is severely impacting our ability to successfully treat common infections. Herein, we report the antibacterial activity against S. aureus and E. faecalis (including some MDR strains) of a panel of adarotene-related synthetic retinoids. In many cases, these compounds showed, together with favorable MICs, a detectable bactericidal effect. We found that the pattern of substitution on adarotene could be modulated to obtain selectivity for antibacterial over the known anticancer activity of these compounds. NMR experiments allowed us to define the interaction between adarotene and a model of microorganism membrane. Biological assessment confirmed that the scaffold of adarotene is promising for further developments of non-toxic antimicrobials active on MDR strains

Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors

Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability

Embelin as lead compound for new neuroserpin polymerization inhibitors

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic reticulum of neurons in the central nervous system. To date, embelin (EMB) is the only known inhibitor of NS polymerization in vitro. This molecule is capable of preventing NS polymerization and dissolving preformed polymers. Here, we show that lowering EMB concentration results in increasing size of NS oligomers in vitro. Moreover, we observe that in cells expressing NS, the polymerization of G392E NS is reduced, but this effect is mediated by an increased proteasomal degradation rather than polymerization impairment. For these reasons we designed a systematic chemical evolution of the EMB scaffold aimed to improve its anti-polymerization properties. The effect of EMB analogs against NS polymerization was assessed in vitro. None of the EMB analogs displayed an anti-polymerization activity better than the one reported for EMB, indicating that the EMB–NS interaction surface is very specific and highly optimized. Thus, our results indicate that EMB is, to date, still the best candidate for developing a treatment against NS polymerization

Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic reticulum of neurons in the central nervous system. To date, embelin (EMB) is the only known inhibitor of NS polymerization in vitro. This molecule is capable of preventing NS polymerization and dissolving preformed polymers. Here, we show that lowering EMB concentration results in increasing size of NS oligomers in vitro. Moreover, we observe that in cells expressing NS, the polymerization of G392E NS is reduced, but this effect is mediated by an increased proteasomal degradation rather than polymerization impairment. For these reasons we designed a systematic chemical evolution of the EMB scaffold aimed to improve its anti-polymerization properties. The effect of EMB analogs against NS polymerization was assessed in vitro. None of the EMB analogs displayed an anti-polymerization activity better than the one reported for EMB, indicating that the EMB\u2013NS interaction surface is very specific and highly optimized. Thus, our results indicate that EMB is, to date, still the best candidate for developing a treatment against NS polymerizatio

Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors

A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation

A Modus Vivendi? Sex, Marriage & the Church

During the 1960s, nearly 80 percent of adult Americans were married. A recent analysis of U.S. census data reported that only 52 percent of adult Americans were married in 2009. That is the lowest percentage reported in the 100 years the Census Bureau has collected such information. The reasons for this dramatic cultural shift are well known: high rates of divorce; changing attitudes toward premarital sex; social acceptability of cohabitation; the weakening of the stigma surrounding out-of-wedlock births and single parenting; the postponement of marriage and children for academic or professional reasons. Among those with only a high-school education or less, the data suggest that the decision to marry has been made more difficult by deteriorating economic conditions

Cover Story: A Modus Vivendi? Sex, Marriage and the Church

The article presents divergent views on an analysis by historian Eamon Duffy of the Catholic Church\u27s response to shifting attitude towards sex and marriage in the West. Duffy noted that the church is increasingly confronted with the need to evolve a modus vivendi with social trends. Many Catholics are said to have disregarded the church\u27s teachings on sex and marriage. Other topics tackled include the increasing rate of divorce, premarital sex, same-sex unions and sexual education

Biphenyl-4-yl-acrylohydroxamic acids: identification of a novel indolyl-substituted HDAC inhibitor with antitumor activity

Modification of the cap group of biphenylacrylohydroxamic acid-based HDAC inhibitors led to the identification of a new derivative (3) characterized by an indolyl-substituted 4-phenylcinnamic skeleton. Molecular docking was used to predict the optimal conformation in the class I HDACs active site. Compound 3 showed HDAC inhibitory activity and antiproliferative activity against a panel of tumor cell lines, in the low \u3bcM range. The compound was further tested in vitro for acetylation of histone H4 and other non-histone proteins, and in vivo in a colon carcinoma model, showing significant proapoptotic and antitumor activities

7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors

7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals