Identification of new anti-Candida compounds by ligand-based pharmacophore virtual screening

Candida albicans represents the most prevalent microbial population in mucosal and systemic infections, usually confined to severely immunocompromised people. Considering the increase of resistant strains and the demand for new antifungal drugs endowed with innovative mechanism of action, we performed a ligand-based virtual screening in order to identify new anti-Candida compounds. Starting from a large library of natural/semisynthetic products and several published synthesized compounds, three coumarin derivatives were discovered in silico as new hit compounds and submitted to the in vitro assay in order to confirm their predicted biological activity

Synthesis and biological evaluation of new 3(2H)-pyridazinone derivatives as non-toxic anti-proliferative compounds against human colon carcinoma HCT116 cells

Novel 3(2H)-pyridazinone derivatives were designed, synthesised in satisfactory yields and evaluated in different experimental assays to assess their preliminary toxicity in vivo and anti-proliferative effects against HCT116 cell lines in vitro. Artemia salina lethality test provided LC50 values >100 mu g/mL for all compounds. Successive assays revealed that some compounds were endowed with a promising anti-proliferative effect against HCT116 cells, alone or stimulated by serotonin as a pro-inflammatory factor in order to mimick an inflamed model in vivo of cancer cell microenvironment. Moreover, the kinurenic acid level after treatment with these newly synthesised compounds was monitored as a marker of anti-proliferation in colon carcinoma models. The IC50 values obtained for the best-in-class compounds were comparable to that of daunorubicin as a reference drug. Conversely, these compounds were not able to counteract the spontaneous migration of human cancer HCT116 cell line in the wound healing paradigm

Investigation on the stability of new biologically active thiosemicarbazone-derived compounds by a validated HPLC-PDA method

New Chemical Entities (NCEs) could be generally exposed to several stress conditions of hydrolysis, oxidation, photolysis and thermal degradation in order to better characterize the compounds and to know if the degradation processes lead to generate undesired (or toxic) products

38. A Novel Histone Acetyltransferase Inhibitor Modulating Gcn5 Network: Cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl)hydrazone

Acetylation is a key modulator of genome accessibility through decondensation of the chromatin structure. The balance between acetylation and opposite deacetylation is, in fact, a prerequisite for several cell functions and differentiation. To find modulators of the histone acetyltransferase Gcn5p, we performed a phenotypic screening on a set of newly synthesized molecules derived from thiazole in budding yeast Saccharomyces cereVisiae. We selected compounds that induce growth inhibition in yeast strains deleted in genes encoding known histone acetyltransferases. A novel molecule CPTH2, cyclopentylidene-[4-(4′-chlorophenyl)thiazol- 2-yl)hydrazone, was selected based on its inhibitory effect on the growth of a gcn5Δ strain. We demonstrated a specific chemical-genetic interaction between CPTH2 and HAT Gcn5p, indicating that CPTH2 inhibits the Gcn5p dependent functional network. CPTH2 inhibited an in vitro HAT reaction, which is reverted by increasing concentration of histone H3. In vivo, it decreased acetylation of bulk histone H3 at the specific H3-AcK14 site. On the whole, our results demonstrate that CPTH2 is a novel HAT inhibitor modulating Gcn5p network in vitro and in vivo