No abstract

Literature surveys indicate that quinoline derivatives possess diverse pharmacological activities, including antimicrobial (1), antimalarial (2), antiviral (3), antitumor (4), immunomodulatory (5), caspase-3 inhibition (6), antileishmanial (7), local anesthetic (8), antiarrhythmic (8) and anti-inflammatory activities (9). Also, thiosemicarbazones constitute one of the most versatile classes of compounds possessing a wide spectrum of activities. It has been reported that thiosemicarbazone derivatives possess antimicrobial (1, 10), antimalarial (11), antiamoebic (12) and antitumor (13) activities. They have been in the focus of interest of medicinal chemists in the past decades because of the outstanding biological activities exhibited by several derivatives incorporating the heterocyclic moiety. Similarly, it is well documented that thiazoline nucleus is associated with a vari- 5-Acyl-8-hydroxyquinoline-2-(3'-substituted-4'-aryl-2,3--dihydrothiazol-2'-ylidene)hydrazones, 5a-e to 10a-c, were prepared by the reaction of appropriate 5-acyl-8-hydroxyquinoline-4-substituted thiosemicarbazones 3a-e and phenacyl bromides 4a-e. Structures of the new compounds were verified on the basis of spectral and elemental analyses. Twenty-eight new compounds were tested for their possible antimicrobial activities. Most of the tested compounds showed weak to moderate antibacterial activity against most of the bacterial strains used in comparison with gatifloxacin as a reference drug. The test compounds showed weak to moderate antifungal activity against tested fungi in comparison with ketoconazole as a reference drug. On the other hand, the newly synthesized compounds were tested for their anti-inflammatory effects and most of them showed good to excellent anti-inflammatory activity compared to indomethacin. Moreover, ulcerogenicity and the median lethal dose (LD 50 ) of the most active anti-inflammatory compounds 6b and 9e were determined in mice; they were non-toxic at doses up to 400 mg kg -1 after i.p. administration.

Cancer is often associated with an aberrant increase in tubulin and microtubule activity required for cell migration, invasion, and metastasis. A new series of fatty acid conjugated chalcones have been designed as tubulin polymerization inhibitors and anticancer candidates. These conjugates were designed to harness the beneficial physicochemical properties, ease of synthesis, and tubulin inhibitory activity of two classes of natural components. New lipidated chalcones were synthesized from 4-aminoacetophenone via N-acylation followed by condensation with different aromatic aldehydes. All new compounds showed strong inhibition of tubulin polymerization and antiproliferative activity against breast and lung cancer cell lines (MCF-7 and A549) at low or sub-micromolar concentrations. A significant apoptotic effect was shown using a flow cytometry assay that corresponded to cytotoxicity against cancer cell lines, as indicated by a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. Decanoic acid conjugates were more potent than longer lipid analogues, with the most active being more potent than the reference tubulin inhibitor, combretastatin-A4 and the anticancer drug, doxorubicin. None of the newly synthesized compounds caused any detectable cytotoxicity against the normal cell line (Wi-38) or hemolysis of red blood cells below 100 μM. It is unlikely that the new conjugates described would affect normal cells or interrupt with cell membranes due to their lipidic nature. A quantitative structure-activity relationship analysis was performed to determine the influence of 315 descriptors of the physicochemical properties of the new conjugates on their tubulin inhibitory activity. The obtained model revealed a strong correlation between the tubulin inhibitory activity of the investigated compounds and their dipole moment and degree of reactivity.