Dimitrios Galanakis

Synthesis and pharmacological evaluation of novel derivatives of anti-inflammatory drugs with increased antioxidant and anti-inflammatory activities

The role of reactive oxygen species in inflammatory processes has been well documented, while several antioxidant compounds have been shown to exhibit anti‐inflammatory activity. We designed novel compounds as potential agents that combine enhanced antioxidant and anti‐inflammatory activities. Derivatives of indomethacin, diclofenac, tolfenamic acid, and ibuprofen, four widely used nonsteroidal anti‐inflammatory drugs, with cysteamine, a polar antioxidant molecule, were synthesized. The compounds were evaluated for their effect on free radical processes (protection against rat hepatic microsomal lipid‐peroxidation and interaction with the stable free radical 1,1‐diphenyl‐2‐picrylhydrazyl), as well as on carrageenan‐induced inflammation (mouse paw edema inhibition). Furthermore, ulcerogenicity tests in rats were performed in order to evaluate the gastrointestinal irritation of the novel indomentacin derivative. It was found that all compounds were very potent antioxidants in vitro; they could inhibit lipid peroxidation very significantly, having IC50 values ranging from 55 to 510 μM, while they could also interact ∼90% with DPPH at equimolar concentrations. We attribute these activities to their sulfhydryl group, as well as to their increased lipophilicity compared to cysteamine. Furthermore, the derivatives demonstrated significant anti‐inflammatory activity, comparable to that of the parent molecules, while they showed significantly reduced ulcerogenic potency. Our results indicate that the combined pharmacological properties of these new derivatives may prove useful for the design and development of novel cytoprotective/anti‐inflammatory molecules with potentially important therapeutic applications. Drug Dev. Res. 47:9–16, 1999.

Reduction of gastrointestinal toxicity of NSAIDs via molecular modifications leading to antioxidant anti-inflammatory drugs

Reactive oxygen species and free radical reactions are related to several pathologic conditions including inflammation and gastric ulceration. The latter is the major undesired side-effect of almost all NSAIDs. Since this effect of NSAIDs is greatly influenced not only by the type of cyclooxygenase which is inhibited but also by the acidic nature of the molecule, we considered it interesting to modify their structure in such a way that it would lead to an antioxidant, neutral molecule or a molecule with greatly reduced acidic character. Thus, we synthesized amide derivatives of four well-known NSAIDs, i.e. diclofenac acid, tolfenamic acid, ibuprofen and indomethacin, with cysteamine, a well-known antioxidant. The synthesized derivatives, with demonstrated good anti-inflammatory and antioxidant activities, showed very significant reduction of ulcerogenicity in the investigation of gastrointestinal (GI) toxicity. As indices of ulcerogenic toxicity in rats, we used the mortality (%), the incidence of GI ulcers (%), body weight reduction (g/100 g BW) and the incidence of melena. All amide derivatives of the NSAIDs with cysteamine were almost non-toxic in the GI tract, under our experimental conditions, in contrast to their parent NSAIDs. These results are attributed to the acquired antioxidant activity as well as to the reduction of acidic character compared with the parent compounds. Therefore, it can be concluded that the combination of these two properties, anti-inflammatory and antioxidant activity, with a simultaneous drastic reduction of acidic character, may lead to the development of novel, useful anti-inflammatory and cytoprotective pharmacomolecules, with potentially important therapeutic applications.

Compounds that block both intermediate-conductance (IKCa) and small-conductance (SKCa) calcium-activated potassium channels

Nine bis‐quinolinyl and bis‐quinolinium compounds related to dequalinium, and previously shown to block apamin‐sensitive small conductance Ca2+‐activated K+ channels (SKCa), have been tested for their inhibitory effects on actions mediated by intermediate conductance Ca2+‐activated K+ channels (IKCa) in rabbit blood cells. In most experiments, a K+‐sensitive electrode was employed to monitor the IKCa‐mediated net loss of cell K+ that followed the addition of the Ca2+ ionophore A23187 (2 μM) to red cells suspended at an haematocrit of 1% in a low K+ (0.12–0.17 mM) solution. The remainder used an optical method based on measuring the reduction in light transmission that occurred on applying A23187 (0.4 or 2 μM) to a very dilute suspension of red cells (haematocrit 0.02%). Of the compounds tested, the most potent IKCa blocker was 1,12 bis[(2‐methylquinolin‐4‐yl)amino]dodecane (UCL 1407) which had an IC50 of 0.85±0.06 μM (mean±s.d.mean). The inhibitory action of UCL 1407 and its three most active congeners was characterized by (i) a Hill slope greater than unity, (ii) sensitivity to an increase in external [K+], and (iii) a time course of onset that suggested use‐dependence. Also, the potency of the nonquaternary compounds tested increased with their predicted lipophilicity. These findings suggested that the IKCa blocking action resembles that of cetiedil rather than of clotrimazole. Some quaternized members of the series were also active. The most potent was the monoquaternary UCL 1440 ((1‐[N‐[1‐(3,5‐dimethoxybenzyl)‐2‐methylquinolinium‐4‐yl]amino]‐10‐[N′‐(2‐methylquinolinium‐4yl)amino] decane (trifluoroacetate) which had an IC50 of 1.8±0.1 μM. The corresponding bisquaternary UCL 1438 (1,10‐bis[N‐[1‐(3,5‐dimethoxybenzyl)‐2‐methylquinolinium‐4‐yl]amino] decane bis(trifluoroacetate) was almost as active (IC50 2.7±0.3 μM). A bis‐aminoquinolium cyclophane (UCL 1684) had little IKCa blocking action despite its great potency at SKCa channels (IC50 4.1±0.2 nM). The main outcome is the identification of new intermediate‐conductance Ca2+‐activated K+ channel blockers with a wide range of IKCa/SKCa selectivities.

Synthesis and qsar of dequalinium analogues AS K+ channel blockers. investigations on the role of the 4-amino group

Dequalinium (1) is a potent and selective non-peptidic blocker of the SKCa channel. The contribution of the 4-amino group to activity was investigated by replacing it by other groups R4. The size or lipophilicity of R4 was found to be unimportant and a good correlation was obtained between σR for R4 and the blocking potency of the analogues, suggesting that the role of the NH2 group is electronic.

Bis-quinolinium cyclophanes: A novel class of potent blockers of the apamin-sensitive Ca2+-activated K+ channel

Abstract Based on the structure-activity analysis of two series of blockers of the small conductance Ca2+-activated K+ (SKCa) channel, a novel class of bis-quinolinium cyclophane blockers has been designed and synthesised. These compounds exhibit submicromolar activity; UCL 1530 (4) is a useful agent since it has been shown (elsewhere) to be selective for the neuronal SKCa channel (IC50 = 80 nM) relative to hepatocyte channels.

Two-dimensional NMR analysis of selected dequalinium analogues having aralkyl linking groups

The 1H signals of the 4‐aminoquinolinium moieties and the 13C signals of the title compounds were fully assigned, using the concerted application of one‐ and two‐dimensional NMR techniques, including nuclear Overhauser effect difference, DEPT, COSY, HETCOR and long‐range 13C–1H correlation spectroscopy. The effect that quaternization of the endocyclic nitrogen atom has on the resonances of the proton and carbon atoms of the 4‐aminoquinoline ring is reported. Atomic charges of the heterocyclic moiety of model compounds such as 4AQ, 4AQ.HBr and 4‐amino‐1‐benzylquinolinium bromide (8) are shown to be linearly related to 13C chemical shifts.