Synthesis And Anti-proliferative Activity Of Fluoroquinolone C3 (Rhodanine Unsaturated Ketone) Amide Derivatives

The development of new drugs is originated in the discovery of lead compounds, and the rational drug molecular designs which base on the structure and mechanism were proved to be an effective way to receive lead compounds. The significant strategies of pharmacophore splice and bioisosteric replacement principle in the basis of the molecular structure of approved drugs are applied to design and synthetize lead compounds possessed new structure.As a kind of clinical widely used total synthetic antimicrobials, fluoroquinolones performed antibacterial effect by inhibiting bacterial DNA gyrase. Being the target of a variety of clinical antitumor drugs, Topoisomerase II was similar to bacterial DNA gyrase on structure and function. Thus, it is expected to transform its antibacterial action into the anticancer activity through structure modifications. In addition,the structure modifications about mother nucleus of fluoroquinolone mostly focused on N-1, C-7 and C-8of quinoline ring. The candidate compounds, which were obtained from the structure modifications on fluoroquinolone, failed to enter clinical evaluation phase due to their toxicity in vivo tumor model, inferior stability and other problems. Therefore, searching for a new structure modification strategy to reduce their toxicity and increase stability was significant to develop antineoplastic quinolone. Fortunately, previous studies found that fluoroquinolone C-3 carboxyl is not necessary for antitumor activity and can be replaced by bioisosteric such as amide groups. Furthermore, rhodanines(TZDS) has became a favour molecular because of its extensive pharmacological activities. So we considered connecting rhodanine to the end of the fluoroquinolone amide and introducing another important pharmacophore-α, β-unsaturated ketone structure on its C-5(i.e., the alpha bits of carbonyl) through Claisen-Schmidt condensation. As a result, the fluoroquinolone(rhodamine α, β unsaturated ketones) amide compounds were designed.To discover novel antitumor lead compounds, a series of fluoroquinolone(rhodanine α, β-unsaturated ketone) amine derivatives(4a-4l, 5a-5l) were synthesized with fluoroquinolone amide scaffold as a carrier.The structures of twenty-four title compounds were characterized by HRMS, 1H NMR and IR. The antibacterial activity of the target compounds against Gram-negative bacteria and Gram-positive bacteria in vitro was screened through the K-B experiment method. The anti-proliferative activity against SMMC-7721, Capan-1 and HL60 cells in vitro was evaluated by MTT assay. Cell apoptosis was determined using Hoechst 33258 fluorescence staining and PI method. Mitochondrial membrane potential was measured using a high content screening image system.24 target compounds were synthesized and theirstructures confirmed by HRMS, 1H NMR and IR. The results of anti-bacterial acitivity in vitro showed that: the compounds exhibited worse acitivity than control. But, the results of anti-cancer acitivity showed that the title compounds had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin and levofloxacin. Especially, these coupounds exhibited the highest activity against Capan-1 cells. The SAR revealed that the anti-proliferation activity of some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing trifluoromethyl or nitryl(5i, 5j, 5k) were comparable to Sunitinib against Capan-1 cells. As such, it suggests that fluoroquinolone(rhodanine α, β-unsaturated ketone) amines are promising lead compounds for the development of novel antitumor fluoroquinolones or rhodanine analogues.