Synthesis of Novel 8-Hydroxyquinoline Derivatives through Mannich Reaction and their Biological Evaluation as Potential Immunomodulatory Agents.

BACKGROUND: In continuation of our work on Mannich reaction on 8-hydroxyquinoline, fifteen different combinations of aromatic aldehydes and aniline were subjected to Mannich reaction from which twelve products (eight Mannich bases, two imines and two intramolecularly cyclized products with benzofuranone skeleton) were obtained. Among them six compounds (1, 2, 6, 8, 9 and 12) are the new compounds. The structures of the compounds were characterized by UV, IR, MS and 1H NMR. METHODS: The compounds were tested for the inhibition of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and Interleukin-1ß (IL-1ß) at a concentration of 25 µg/mL. The cytokines were produced by THP-1 cells differentiated with PMA for 24hrs and stimulated with LPS for 4 hrs and supernatant were analyzed through ELISA technique. RESULTS AND DISCUSSION: Compounds 1-5, 8 and 9 inhibited the production of TNF-α and IL-1ß. Compounds 1, 3, and 8 exerted potent inhibitions of TNF-α with 71%, 71%, and 83% inhibition, respectively. Compounds 1 and 8 significantly inhibited the production of IL-1ß with 64% and 78% inhibition, respectively. CONCLUSION: Compounds 1 and 8 significantly inhibited the production of IL-1ß with 64% and 78% inhibition, respectively. Notably compound 8 showed the most potent inhibition of these cytokines. Additionally, the effect of compounds on viability of THP-1 cells was also evaluated. Moreover, molecular docking was carried out to study the mechanism of inhibition of TNF-α production.

The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies.

Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti-bacterial, and anti-allergic activities. The objective of the present study was to evaluate effects of benzothiazole analogs (compounds 1-26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8-10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC50 ranging from 3.7 to 11.9 µM compared to that of the standard drug, prednisolone <1.5 µM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC50 values ranging between <4.0 and 12.8 µM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC50 values between <4.0 and 15.2 µM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 µg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P<0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC50 range of <4.0 to 40.3 µM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naïve T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases.

Cheiradone: a vascular endothelial cell growth factor receptor antagonist.

BACKGROUND: Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with physiological (for example wound healing) and pathological conditions (tumour development). Vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) are the major angiogenic regulators. We have identified a natural product (cheiradone) isolated from a Euphorbia species which inhibited in vivo and in vitro VEGF- stimulated angiogenesis but had no effect on FGF-2 or EGF activity. Two primary cultures, bovine aortic and human dermal endothelial cells were used in in vitro (proliferation, wound healing, invasion in Matrigel and tube formation) and in vivo (the chick chorioallantoic membrane) models of angiogenesis in the presence of growth factors and cheiradone. In all cases, the concentration of cheiradone which caused 50% inhibition (IC50) was determined. The effect of cheiradone on the binding of growth factors to their receptors was also investigated. RESULTS: Cheiradone inhibited all stages of VEGF-induced angiogenesis with IC50 values in the range 5.20-7.50 microM but did not inhibit FGF-2 or EGF-induced angiogenesis. It also inhibited VEGF binding to VEGF receptor-1 and 2 with IC50 values of 2.9 and 0.61 microM respectively. CONCLUSION: Cheiradone inhibited VEGF-induced angiogenesis by binding to VEGF receptors -1 and -2 and may be a useful investigative tool to study the specific contribution of VEGF to angiogenesis and may have therapeutic potential.