Discovery of Indeno[1,2-c]quinoline Derivatives as Potent Dual Antituberculosis and Anti-Inflammatory Agents.

Tsong-Long Hwang,Cherng-Chyi Tzeng,Yeh-Long Chen,Chih-Hua Tseng,Yen-Hsu Chen,Chun-Wei Tung,Chen-Hsin Wu

doi:10.3390/molecules22061001

Abstract

A series of indeno[1,2-c]quinoline derivatives were designed, synthesized and evaluated for their anti-tuberculosis (anti-TB) and anti-inflammatory activities. The minimum inhibitory concentration (MIC) of the newly synthesized compound was tested against Mycobacterium tuberculosis H37RV. Among the tested compounds, (E)-N′-[6-(4-hydroxypiperidin-1-yl)-11H-indeno[1,2-c]quinolin-11-ylidene]isonicotino-hydrazide (12), exhibited significant activities against the growth of M. tuberculosis (MIC values of 0.96 μg/mL) with a potency approximately equal to that of isoniazid (INH), an anti-TB drug. Important structure features were analyzed by quantitative structure–activity relationship (QSAR) analysis to give better insights into the structure determinants for predicting the anti-TB activity. The anti-inflammatory activity was induced by superoxide anion generation and neutrophil elastase (NE) release using the formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils method. Results indicated that compound 12 demonstrated a potent dual inhibitory effect on NE release and superoxide anion generation with IC50 values of 1.76 and 1.72 μM, respectively. Our results indicated that compound 12 is a potential lead compound for the discovery of dual anti-TB and anti-inflammatory drug candidates. In addition, 6-[3-(hydroxymethyl)piperidin-1-yl]-9-methoxy-11H-indeno[1,2-c]quinolin-11-one (4g) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC50 values of 0.46 and 0.68 μM, respectively, and is a potential lead compound for the discovery of anti-inflammatory drug candidates.

Highlights

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis which primarily affects the lungs, causing an intense local inflammatory response that is critical to the pathogenesis of tuberculosis [1,2]
According to our previously reported procedures [29], 2-hydroxy-3-phenylquinoline-4-carboxylic acid was treated with POCl3 to afford 6-chloro-11H-indeno[1,2-c]quinolin-11-one (1), which was reacted with cyclic amines to give 6-cycloamino-11H-indeno[1,2-c]quinolin-11-ones (3a–3g)
2017, (4-hydroxypiperidin-1-yl)-11H-indeno[1,2-c]quinolin-11-one oxime (7) and (E)-6-(4-hydroxypiperidin1-yl)-11H-indeno[1,2-c]quinolin-11-one O-methyl oxime (8) were obtained from 3d by the

Summary

Introduction

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis which primarily affects the lungs, causing an intense local inflammatory response that is critical to the pathogenesis of tuberculosis [1,2]. Anti-inflammatory drugs, especially corticosteroids, are currently used for adjunctive therapy in most severe life-threatening forms of tuberculosis, such as meningitis and pericarditis [4]. The importance of developing new drugs with dual anti-inflammatory and antimycobacterial activities is amplified by the emergence of multi-drug resistant (MDR) strains and the global human immunodeficiency virus (HIV) pandemic [5,6,7]. The anti-leprosy drug clofazimine [8] exhibited dual anti-inflammatory and antimycobacterial activities. Its potency is not sufficient, motivating the design and search for novel agents

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