To increase the efficacy and decrease the side effects of non-steroidal anti-inflammatory drugs NSAIDs in the treatment of inflammatory diseases, several chemical structure modifications can be made. These modifications aim to improve the pharmacokinetic and pharmacodynamic properties of the drugs, as well as minimize their gastrointestinal, renal, and cardiovascular side effects. Some of the possible modifications include:1. Selective COX-2 inhibition: NSAIDs work by inhibiting cyclooxygenase COX enzymes, which are responsible for the production of prostaglandins that cause inflammation, pain, and fever. There are two main isoforms of COX: COX-1 and COX-2. COX-1 is constitutively expressed and has a protective role in the gastrointestinal tract, while COX-2 is induced during inflammation. Designing drugs that selectively inhibit COX-2 can help maintain the anti-inflammatory effects while reducing gastrointestinal side effects.2. Prodrug approach: Developing prodrugs, which are biologically inactive compounds that are converted into active drugs in the body, can improve the pharmacokinetic properties of NSAIDs. This approach can help increase drug solubility, absorption, and distribution, as well as decrease the potential for gastrointestinal irritation.3. Nitric oxide NO -releasing NSAIDs: Combining NSAIDs with NO-donating moieties can help reduce gastrointestinal side effects. NO has cytoprotective effects in the gastrointestinal tract and can counteract the negative effects of COX inhibition on the gastric mucosa. NO-releasing NSAIDs have shown promising results in preclinical studies, with reduced gastrointestinal toxicity compared to traditional NSAIDs.4. Hydrogen sulfide H2S -releasing NSAIDs: Similar to NO-releasing NSAIDs, H2S-releasing NSAIDs have been developed to reduce gastrointestinal side effects. H2S has been shown to have anti-inflammatory and cytoprotective effects in the gastrointestinal tract. Combining H2S-releasing moieties with NSAIDs can help maintain their anti-inflammatory effects while reducing gastrointestinal toxicity.5. Dual-action drugs: Designing drugs that have dual-action mechanisms can help increase efficacy and decrease side effects. For example, combining an NSAID with a histamine H2 receptor antagonist can help reduce gastrointestinal side effects by inhibiting gastric acid secretion. Another example is the development of dual COX/lipoxygenase LOX inhibitors, which can target both the COX and LOX pathways involved in inflammation, potentially providing greater anti-inflammatory effects.6. Targeted drug delivery systems: Developing targeted drug delivery systems, such as nanoparticles or liposomes, can help improve the pharmacokinetic properties of NSAIDs and minimize their side effects. These systems can help increase drug solubility, prolong drug release, and target specific sites of inflammation, thereby reducing systemic exposure and decreasing the potential for side effects.In conclusion, modifying the chemical structure of NSAIDs can help increase their efficacy and decrease their side effects in the treatment of inflammatory diseases. These modifications can involve selective COX-2 inhibition, prodrug development, NO- or H2S-releasing moieties, dual-action drugs, and targeted drug delivery systems. Further research and development of these modified NSAIDs can potentially lead to safer and more effective treatments for patients suffering from inflammatory diseases.