Lead Optimization on Conventional Non‐Steroidal Anti‐Inflammatory Drugs: An Approach to Reduce Gastrointestinal Toxicity

Abstract

Non-steroidal anti-inflammatory drugs are among the most widely used therapeutics, primarily for the treatment for pain and inflammation. Prostaglandins mediate a number of characteristic features of the body's response to tissue injury or inflammation. These outstanding effects include their cytoprotective properties in the gastrointestinal tract and control of renal functions in the kidney. Non-steroidal anti-inflammatory drugs exert their anti-inflammatory and antipyretic effects by blocking the production of prostanoids from arachidonic acid through inhibition ofcyclooxygenase enzyme. Classic non-steroidal anti-inflammatory drugs such as meclofenamic acid and indomethacin inhibit both isoforms of cyclooxygenase non-selectively or with low selectivity, exerting their anti-inflammatory activity via inhibiting cyclooxygenase-2, and their deleterious side-effects by inhibiting cyclooxygenase-1. To provide an effective treatment for inflammatory disorders, the design of novel non-steroidal anti-inflammatory drugs is aimed at obtaining new drugs, devoid of the side-effects commonly associated with conventional non-steroidal anti-inflammatory drugs. Several approaches have been explored to counteract the gastric damaging effects of these drugs. The chemical modification of non-steroidal anti-inflammatory drugs is aimed at improving their safety profile, where several studies have described the derivatization of the carboxylate function of non-steroidal anti-inflammatory drugs with less acidic analogs, which resulted in an increased anti-inflammatory activity with reduced ulcerogenicity. The present review explores the possible ways aimed to reduce ulcerogenicity.

Anthocyanin-containing purple-fleshed potatoes suppress colon tumorigenesis via elimination of colon cancer stem cells

“…However, long-term use of NSAIDs, in particular sulindac, is associated with adverse gastrointestinal and renal toxicities [10,11]. Conversely, as colon cancer involves stepwise mutations in multiple genes, there is a long latency period [12,13] before it manifests and thus there is an opportunity to target colon cancer by suitable A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT modification of diet.…”

Insects: an underrepresented resource for the discovery of biologically active natural products

“…7) and five known dopamine dimers ( 24, 36 -- 39 ) isolated from Blaps japanensis were evaluated for their activity against cyclooxygenase (COX) enzymes: COX-1 and COX-2 90 . Cyclooxygenases are responsible for catalyzing the conversion of arachidonic acid to prostaglandins, important mediators of pain, fever, and inflammation 91 . The COX-1 isoform is expressed constitutively in tissues and is responsible for maintaining a homeostatic concentration of prostaglandins.…”

Synthesis and cycloxygenase inhibitory properties of new naphthalene-methylsulfonamido, naphthalene-methylsulfonyl and tetrahydronaphthalen-methylsulfonamido compounds

“…A solution of 3-Nitro-naphthalene-1-carboxylic acid 22 8 (3 g, 0.014 mol) in SOCl 2 (18 ml) was refluxed for 3 h. The thionyl chloride was evaporated under reduced pressure, and the solid obtained, triturated with hexane, gave 23 that was purified by crystallization from CCl 4 General procedure for the synthesis of 4-benzoyl-2-naphthylamines (26a-c)…”

“…Particular attention has been recently focused on the role that COX-2 enzyme could play in Alzheimer's diseases (AD) 2,3 . After the removal from the market of some selective COX-2 inhibitors (COXIBs), due to their cardiovascular side effects, the research has focused towards the evaluation of alternative chemical structures able to maintain the COX inhibitory activity with reduced side effects 4 . With this aim, we synthesized a series of new naphthalene derivatives naproxene and 6-methoxy naphthalene acetic acid-like (6-MNA; 1-6; Figure 1).…”

“…With this aim, we synthesized a series of new naphthalene derivatives naproxene and 6-methoxy naphthalene acetic acid-like (6-MNA; 1-6; Figure 1). In these compounds, the carboxylic function, typical of the classical NSAIDs, was replaced by a methylsulfonamido (1, 2, 6a-c) or methylsulfonyl (3)(4)(5) group present in some selective COX-2 inhibitors as for example NS398 or SC-57666, respectively. We also synthesized the methylsulfonamido compounds 7 and 8 in which the naphthalene portion was substituted by tetrahydronaphthalene ring.…”