1-hydroxy-5, 7-dimethoxy-2 naphthalene-carboxaldehyde inhibitors as novel antimycobacterial agents targeting H-InMyoFib cells and targeting enzymes involved in fatty acid biosynthesis of bacilli

Abstract

Background: Gastrointestinal tuberculosis (Gastrointestinal TB) is a rapidly common infectious disease in low income countries due to poor life style that poses diagnostic challenge, as the broad spectrum features of the disease which may lead to diagnostic interruptions and complications. Early diagnosis and initiation of antituberculous therapy without drug-resistance is essential to prevent morbidity and mortality. 1-hydroxy-5, 7-dimethoxy-2 naphthalene-carboxaldehyde (HDNC) is a bioactive compound derived from Aegle marmelos (Rutaceae, ‘Bael’). It is a naturally occurring flavonoid having anticancer and wound healing properties. Methods & Materials: The present study demonstrated that HDNC had ant-mycobacterial effects on tubercle bacilli ATCC25618, multi-drug and extensively drugresistant clinical isolates with minimum inhibitory concentrations of 147 and 312 μM, respectively. Bacilli mainly affect the GIT, causing a strong local inflammatory response that is critical to the pathogenesis of tuberculosis. Results: We investigated the effects of HDNC on interferon (IFN)-γ-stimulated human GIT fibroblast H-InMyoFib cells. HDNC suppressed the release of tumor necrosis factor (TNF)-α and interleukin (IL)-12. A nontoxic dose of HDNC reduced mRNA expression of TNF-α, IL-1β, IL-6, IL-12, and matrix metalloproteinase-1 in IFN-γ-stimulated cells. HDNC inhibited IFN-γ-mediated stimulation of extracellular signal regulated kinase and p38 mitogen-activated protein kinase and showed high affinity binding to these kinases (binding constants: 3.95 × 104 M−1 and 6.8 × 103 M−1, respectively).HDNC inhibit targeting enzymes involved in fatty acid biosynthesis, such as enoyl-ACP-reductase, b-ketoacyl-ACP reductase and b-hydroxyacyl-ACP dehydratase of bacilli. A mouse in vivo study of lipopolysaccharide-induced GIT inflammation revealed that a nontoxic dose of HDNC reduced the levels of IL-1β, IL-6, IL-12, and INF-γ in GIT tissue. Conclusion: Gastrointestinal TB is generally managed with medical therapy with antituberculous drugs These data provide the first evidence that HDNC could be developed as a potent antituberculosis drug and represents as a strong candidate for the b-hydroxyacyl-ACP dehydratase enzyme of Bacilli.