Benzo[d]isothiazole 1,1-dioxide derivatives as dual functional inhibitors of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1

doi:10.1016/j.bmcl.2014.04.006

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 12, 15 June 2014, Pages 2764-2767

https://doi.org/10.1016/j.bmcl.2014.04.006 Get rights and content

Abstract

A series of 6-nitro-3-(m-tolylamino) benzo[d]isothiazole 1,1-dioxide analogues were synthesized and evaluated for their inhibition activity against 5-lipoxygenase (5-LOX) and microsomal prostaglandin E₂ synthase (mPGES-1). These compounds can inhibit both enzymes with IC₅₀ values ranging from 0.15 to 23.6 μM. One of the most potential compounds, 3g, inhibits 5-LOX and mPGES-1 with IC₅₀ values of 0.6 μM, 2.1 μM, respectively.

Graphical abstract

Section snippets

Acknowledgments

This research was supported, in part, by the Ministry of Science and Technology of China (Grant numbers: 2012AA020308, 2009CB918503) and the National Science Foundation of China (Grant numbers: 20873003, 11021463).

References and notes (24)

O. Rådmark et al.
J. Lipid Res.
(2009)
O. Rådmark et al.
Trends Biochem. Sci.
(2007)
M. Murakami et al.
Prog. Lipid Res.
(2004)
A. Koeberle et al.
Bioorg. Med. Chem.
(2009)
C.D. Haffner et al.
Bioorg. Med. Chem. Lett.
(2010)
R.A. Pufahl et al.
Anal. Biochem.
(2007)
C.D. Funk
Science
(2001)
D. Steinhilber
Curr. Med. Chem.
(1999)
C. Pergola et al.
Expert Opin. Ther. Pat.
(2010)
R.W. Friesen et al.
J. Med. Chem.
(2008)

A.V. Sampey et al.

Arthritis Res. Ther.

(2005)

K.D. Rainsford

Subcell. Biochem.

(2007)

Cited by (33)

Supporting-electrolyte-free electrochemical [2 + 2 + 1] annulation of benzo[d]isothiazole 1,1-dioxides, N-arylglycines and paraformaldehyde
2024, Chinese Chemical Letters
Microsomal prostaglandin E<inf>2</inf> synthase-1 and its inhibitors: Molecular mechanisms and therapeutic significance
2022, Pharmacological Research
Citation Excerpt :
Furthermore, compound 12 (10.0 μM) had a good oral bioavailability (72%) without cytotoxicity [128]. Compound 3 g, a 6-nitro-3-(m-tolylamino)benzo[d]isothiazole1,1-dioxide analog, inhibited 5-LOX and mPGES-1 (IC50 = 0.6 μM, 2.1 μM, respectively) [129]. A summary is shown in Table 6.
Inflammation is closely linked to the abnormal phospholipid metabolism chain of cyclooxygenase-2/microsomal prostaglandin E₂ synthase-1/prostaglandin E₂ (COX-2/mPGES-1/PGE₂). In clinical practice, non-steroidal anti-inflammatory drugs (NSAIDs) as upstream COX-2 enzyme activity inhibitors are widely used to block COX-2 cascade to relieve inflammatory response. However, NSAIDs could also cause cardiovascular and gastrointestinal side effects due to its inhibition on other prostaglandins generation. To avoid this, targeting downstream mPGES-1 instead of upstream COX is preferable to selectively block overexpressed PGE₂ in inflammatory diseases. Some mPGES-1 inhibitor candidates including synthetic compounds, natural products and existing anti-inflammatory drugs have been proved to be effective in in vitro experiments. After 20 years of in-depth research on mPGES-1 and its inhibitors, ISC 27864 have completed phase II clinical trial. In this review, we intend to summarize mPGES-1 inhibitors focused on their inhibitory specificity with perspectives for future drug development.
Assessment of anti-inflammatory-like, antioxidant activities and molecular docking of three alkynyl-substituted 3-ylidene-dihydrobenzo[d]isothiazole 1,1-dioxide derivatives
2021, Chemico-Biological Interactions
Citation Excerpt :
In the case of indole derivatives like melatonin and serotonin, the interactions with the active site of MPO heme involve the ring stacking with the indole ring, enhancing their potency [39]. Structural modification by adding substituent allows to modulate the benzoisothiazoles activity and their binding mode [40,41]. At our best knowledge it is the first time to study the inhibitory action of new alkynyl-substituted 3-ylidene-dihydrobenzo[d]isothiazole 1,1-dioxide derivatives on the activity of MPO enzyme using both docking and experimental approaches.
The presence of enyne and benzoisothiazole functions in the molecular architecture of compounds 1, 2 and 3 were expected to provide biochemical activities. In the present work, we first examined the molecular surface contact of three alkynyl-substituted 3-ylidenedihydrobenzo[d] isothiazole 1,1-dioxides. The analysis of the Hirshfeld surfaces reveals that only compound 3 exhibited a well-defined red spots, indicating intermolecular interactions identified as S–O⋯H, C–H⋯O and C–O⋯H contacts. Comparative fingerprint histograms of the three compounds show that close pair interactions are dominated by C–H⋯H–C contact. By UV–visible analysis, compound 1 showed the most intense absorbances at 407 and 441 nm, respectively. The radical scavenging activity explored in the DPPH test, shows that only 1 exhibited low anti-radical activity. Furthermore, cellular antioxidant capacity of benzoisothiazoles 1–3 was investigated with PMA-activated HL-60 cells using chemiluminescence and fluorescence techniques in the presence of L-012 and Amplex Red probe, respectively. Results highlight that compound 1 exhibited moderate anti-ROS capacity while compounds 2 and 3 enhanced ROS production. The cytotoxicity test performed on HL-60 cells, using the MTS assay, confirmed the lack of toxicity of the tested benzoisothiazole 1 compared to 2 and 3 which show low cytotoxicity (≤30%). Anti-catalytic activity was evaluated by following the inhibitory potential of the benzoisothiazoles on MPO activity and depicted benzoisothiazoles-MPO interactions by docking. Both SIEFED and docking studies demonstrated an anti-catalytic activity of the tested benzoisothiazoles towards MPO with the best activity for compound 2.
Isothiazoles
2021, Comprehensive Heterocyclic Chemistry IV
The information on isothiazoles published from 2008 to 2018 is summarized and reviewed. The chapter begins with a summary of the information from previous editions, which is presented in the same sequence as in previous editions: theoretical methods, experimental structural methods, thermodynamic aspects, structural features. The primary attention is focused on the developments in fields of isothiazole ring formation and the reactivity of isothiazoles. The data on the formation of the isothiazole heterocycle is described in the following sequence: intramolecular cyclization (formation of SN, CC, CS, CN bonds), heterocyclizations [4 + 1], [3 + 2] and synthesis based on other heterocyclic compounds. An extensive section is devoted to the methods of isothiazole functionalization. A separate part is devoted to the synthesis of biologically active compounds and prospective scaffolds of high interest. Additionally, the published data on the metal complexes of isothiazoles is comprehensively summarized and reviewed. Of particular interest is the data on the use of palladium complexes of isothiazoles as catalysts for cross-coupling reactions in aqueous media (“green chemistry”). The latest data presented on isothiazoles will be useful to specialists in different areas, including those that work in the fields of medicinal chemistry and catalysis.
Natural products as inhibitors of prostaglandin E<inf>2</inf> and pro-inflammatory 5-lipoxygenase-derived lipid mediator biosynthesis
2018, Biotechnology Advances
Citation Excerpt :
Moreover, the structurally related derivative YS121 (Koeberle et al., 2008b, 2010) was recently shown to decrease pancreatic intraepithelial neoplasia lesions and tumor growth in KrasG12D mice that were deficient of natural killer T cells (Janakiram et al., 2017). Other structural series of dual mPGES-1/5-LO inhibitors include non-acidic benzo[g]indole-3-carboxylates (Koeberle et al., 2009b), benzo[d]isothiazole-1,1-dioxides (Shang et al., 2014) and synthetic derivatives of natural products, i.e., myrtucommulones (Wiechmann et al., 2015b), curcuminoids (Koeberle et al., 2014) and benzoquinones (Filosa et al., 2015). Very recently, the 4,5-diaryloxazol-3-carboxylate BRP-187 was described to inhibit FLAP and mPGES-1 (Garscha et al., 2016).
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostanoid formation and represent prevalent therapeutics for treatment of inflammatory disorders. However, NSAIDs are afflicted with severe side effects, which might be circumvented by more selective suppression of pro-inflammatory eicosanoid biosynthesis. This concept led to dual inhibitors of microsomal prostaglandin E₂ synthase (mPGES)-1 and 5-lipoxygenase that are crucial enzymes in the biosynthesis of pro-inflammatory prostaglandin E₂ and leukotrienes. The potential of their dual inhibition in light of superior efficacy and safety is discussed. Focus is placed on natural products, for which direct inhibition of mPGES-1 and leukotriene biosynthesis has been confirmed.
One-pot, Pd/Cu-catalysed synthesis of alkynyl-substituted 3-ylidene-dihydrobenzo[d]isothiazole 1,1-dioxides
2017, Tetrahedron Letters
Enyne-substituted benzoisothiazole derivatives have been synthesised under one-pot, operationally simple conditions using 2-iodo-N-(trimethylsilylethynyl)benzenesulfonamides and terminal alkynes as starting materials and a palladium–copper-based catalytic system. The structure of these heterocycles has been demonstrated by NMR spectroscopy and confirmed by X-ray crystallographic analysis. A plausible reaction mechanism has been proposed.

View all citing articles on Scopus

View full text

Benzo[d]isothiazole 1,1-dioxide derivatives as dual functional inhibitors of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1

Abstract

Graphical abstract

Section snippets

Acknowledgments

J. Lipid Res.

Trends Biochem. Sci.

Prog. Lipid Res.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Anal. Biochem.

Science

Curr. Med. Chem.

Expert Opin. Ther. Pat.

J. Med. Chem.

Arthritis Res. Ther.

Subcell. Biochem.

Benzo[d]isothiazole 1,1-dioxide derivatives as dual functional inhibitors of 5-lipoxygenase and microsomal prostaglandin E₂ synthase-1