Design And Synthesis Of Potential N-arylanthranilic Acid Non-steroidal Anti-inflammatory Drugs And Investigation Of Their Polymorphism

Non-Steroidal Anti-Inflammatory Drugs(NSAIDs)are a kind of antipyretic,analgesic,anti-inflammatory drugs that are widely used in the treatment of acute or chronic pain and inflammatory immune diseases.Some NSAIDs are also found to have ramifications in preventing cardiovascular and cerebrovascular diseases,senile stroke,dementia,rectal cancer and so on.At present,improving bioavailability while reducing toxicity is a hot research topic in searching for safe NSAIDs.Drug efficacy is closely related to the crystal form of the drug since different crystal forms of the same compound may have different physical and chemical properties,such as solubility,dissolution rate,chemical stability,physical stability,melting point,density,and so on.So while we synthesize new N-arylanthranilic acid NSAIDs we also explore the possibility of multiple crystals of the synthesized compounds and investigate their potential as new drugs.This approach may facilitate comprehensive research to reduce the potential hazards and achieve maximal drug bioavailability and safety.Based on molecular docking and our previous studies,we chose the Ullmann reaction between halogenated aromatic compounds and anilines with Cu as catalyst to synthesize these N-arylanthranilic acids as potential NSAIDs.We synthesized nine target compounds and characterized them by NMR and IR.Then we applied various crystal growth methods for polymorph screening of these compounds.The most frequently used method was slow evaporation of saturated solutions of these compounds in different solvents in different solvents.At the same time slow cooling and quench cooling were used to assist the screening.The structure of the crystals was analyzed by single-crystal X-ray diffraction and crystal form was confirmed by powder X-ray diffraction.Then differential scanning calorimetry(DSC)was performed to study the relative stability of the crystals.Moreover,quantum chemistry calculations such as conformational scanning,Hirschfeld analysis and lattice energy calculation were carried out to further understand the polymorphis of these compounds.In due time,we will investigate the potential of these N-arylanthranilic acids as non-steroidal anti-inflammatory drugs.