Dehydroabietic Acid (DHA, 1) derivatives are known for their antiproliferative properties, among others. In the context of this work, DHA was initially modified to two key intermediates bearing a C18 methyl ester, a phenol moiety at C12, and an acetyl or formyl group at C13 position. These derivatives allowed us to synthesize a series of DHA-chalcone hybrids, suitable for structure–activity relationship studies (SARS), following their condensation with a variety of aryl-aldehydes and methyl ketones. The antiproliferative evaluation of the synthesized DHA-chalcone hybrids against three breast cancer cell lines (the estrogen-dependent MCF-7 and the estrogen-independent MDA-MB-231 and Hs578T) showed that eight derivatives (33, 35, 37, 38, 39, 41, 43, 44) exhibit low micromolar activity levels (IC50 2.21–11.5 μΜ/MCF-7). For instance, some of them showed better activity compared to the commercial anticancer drug 5-FU against MCF-7 cells (33, 41, 43, 44) and against MDA-MB231 (33 and 41). Hybrid 38 is a promising lead compound for the treatment of MCF-7 breast cancer, exhibiting comparable activity to 5-FU and being 12.9 times less toxic (SI = 22.7). Thus, our findings suggest that DHA-chalcone hybrids are drug candidates worth pursuing for further development in the search for novel breast cancer therapies.

In a previous study published by our group, successful modification of the antibiotic chloramphenicol (CHL) was reported, which was achieved by replacing the dichloroacetyl tail with alpha and beta amino acids, resulting in promising new antibacterial pharmacophores. In this study, CHL was further modified by linking the basic amino acids lysine, ornithine, and histidine to the primary hydroxyl group of CHL via triazole, carbamate, or amide bonding. Our results showed that while linking the basic amino acids retained antibacterial activity, it was somewhat reduced compared to CHL. However, in vitro testing demonstrated that all derivatives were comparable in activity to CHL and competed for the same ribosomal binding site with radioactive chloramphenicol. The amino acid–CHL tethering modes were evaluated either with carbamate (7, 8) derivatives, which exhibited higher activity, or with amide- (4–6) or triazole-bridged compounds (1–3), which were equally potent. Our findings suggest that these new pharmacophores have potential as antimicrobial agents, though further optimization is needed.

To combat the dangerously increasing pathogenic resistance to antibiotics, we developed new pharmacophores by chemically modifying a known antibiotic, which remains to this day the most familiar and productive way for novel antibiotic development. We used as a starting material the chloramphenicol base, which is the free amine group counterpart of the known chloramphenicol molecule antibiotic upon removal of its dichloroacetyl tail. To this free amine group, we tethered alpha- and beta-amino acids, mainly glycine, lysine, histidine, ornithine and/or beta-alanine. Furthermore, we introduced additional modifications to the newly incorporated amine groups either with protecting groups triphenylmethyl- (Trt) and tert-butoxycarbonyl- (Boc) or with the dichloroacetic group found also in the chloramphenicol molecule. The antimicrobial activity of all compounds was tested both in vivo and in vitro, and according to the results, the bis-dichloroacetyl derivative of ornithine displayed the highest antimicrobial activity both in vivo and in vitro and seems to be a dynamic new pharmacophore with room for further modification and development.