The Production of TNF-α and Nitric Oxide in Rat Alveolar Macrophages Is Blunted by Isatin-Glycine Hybrids

Abstract

Background: Alveolar macrophages constitute over 90% of the pulmonary macrophage population and have a significant impact on the initiation of inflammatory responses in the lower respiratory tract. The lipopolysaccharide (LPS)-induced overproduction of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) in alveolar macrophages is implicated in the pathogenesis of inflammatory-mediated pulmonary disorders such as bacterial pneumonitis, chronic obstructive pulmonary disease (COPD), and sarcoidosis. Objectives: This study aimed to develop agents against LPS-induced overexpression of TNF-α and NO in rat alveolar macrophages. A novel series of hybrid compounds 3a - c were designed, synthesized, and biologically evaluated. Methods: The final derivatives 3a-c were synthesized through the condensation of primary amine 2 with ketones 1a-c. Alveolar macrophages were isolated from male Wistar rats by bronchoalveolar lavage. To measure the levels of TNF-α, an ELISA-based technique was used according to the manufacturer’s instructions. The content of NO was accurately measured using the Griess assay. Results: The inhibitory activity of synthesized final derivatives 3a-c against the production rate of TNF-α and NO in rat alveolar macrophages was significant (P < 0.01) and comparable with indomethacin as the reference anti-inflammatory drug. Conclusions: The significant inhibition of TNF-α and NO by compounds 3a-c in rat alveolar macrophages suggests that they could be considered as lead compounds for developing novel anti-inflammatory candidates for patients with bacterial pneumonitis, COPD, and sarcoidosis.