Recent advances in the trifluoromethylation methodology and new CF3-containing drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of COX-2 inhibitors. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships.

http://ijpr.sbmu.ac.ir/article_1047_48da80e362d9fbe2ee049a6f517f139c.pdf

Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships

Catalyst-Free Conjugated Addition of Thiols to α,β-Unsaturated Carbonyl Compounds in Water

Recent advance in oxazole-based medicinal chemistry.

Asymmetric organocatalytic reactions by bifunctional amine-thioureas

The non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation, since the introduction of acetylsalicylic acid in 1899 Traditional (first generation) NSAIDs exert antiinflammatory, analgesic, and antipyretic effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenase (COX-1 and COX-2) isozymes Their use is associated with side effects such as gastrointestinal and renal toxicity A number of selective (second generation) COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc) were developed as safer NSAIDs with improved gastric safety profile Observation of increased cardiovascular risks in APPROVe (Adenomatous Polyp Prevention on Vioxx) study sent tremors and led to voluntary withdrawn of Vioxx (rofecoxib) by Merck from the market in September 2004 followed by Bextra (valdecoxib) in 2005 raising a question on the safety of selective COX-2 inhibitors This leads to the belief that these effects are mechanism based and may be class effect However, some studies suggested association of traditional NSAIDs with similar effects requiring a relook into the whole class of NSAIDs rather than simply victimizing the selective COX-2 inhibitors Recognition of new avenues for selective COX-2 inhibitors such as cancer, Alzheimer's disease, Parkinson's disease, schizophrenia, major depression, ischemic brain injury and diabetic peripheral nephropathy has kindled the interest in these compounds This review highlights the various structural classes of selective COX-2 inhibitors developed during past seven years (2003-2009) with special emphasis on diaryl-hetero/carbo-cyclic class of compounds Molecular modeling aspects are also briefly discussed

Progress in COX-2 Inhibitors: A Journey So Far

The 2-(2-arylphenyl)benzoxazole moiety has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The 2-(2-arylphenyl)benzoxazoles 3a–m have been synthesized by Suzuki reaction of 2-(2-bromophenyl)benzoxazole. Further synthetic manipulation of 3f and 3i led to 3o and 3n, respectively. The compounds 3g, 3n, and 3o selectively inhibited COX-2 with selectivity index of 3n much better than that of the COX-2 selective NSAID celecoxib. The in vivo anti-inflammatory potency of 3g and 3n is comparable to that of celecoxib and the nonselective NSAID diclofenac at two different doses, and 3o showed better potency compared to these clinically used NSAIDs.

/pdf/2-2-arylphenyl-benzoxazole-as-a-novel-anti-inflammatory-4q6g3g3s4w.pdf

2-(2-Arylphenyl)benzoxazole As a Novel Anti-Inflammatory Scaffold: Synthesis and Biological Evaluation.

Copper(II) tetrafluoroborate as a novel and highly efficient catalyst for Michael addition of mercaptans to α,β-unsaturated carbonyl compounds

A series of twenty six structurally diverse α-aminophosphonates have been synthesized and evaluated for in vitro anti-leishmanial activity and cytotoxicity using the MTT assay. Among them, seven compounds (1–7) exhibited anti-leishmanial potency against the L. donovani promastigote with IC50 values in the low micromolar range. The structure–activity relationships were quantitatively evaluated by a statistically reliable CoMFA model with high predictive abilities (r2pred = 0.87, r2ncv = 0.985).

α-Aminophosphonates as novel anti-leishmanial chemotypes: synthesis, biological evaluation, and CoMFA studies

Selectivity control during the formation of 1,2-disubstituted benzimidazoles has been achieved for the reaction of o-phenylenediamine with aldehydes in the presence of solid supported protic acids as catalysts and choosing an appropriate reaction medium. Perchloric acid adsorbed on silica-gel (HClO4–SiO2) was found to be the most effective catalyst system for the synthesis of 1,2-disubstituted benzimidazoles in EtOH at rt. Apart from the catalyst and solvent, the electronic and steric factors of the aldehyde and the electronic factor of the o-phenylenediamine are also significant contributory factors in dictating the selectivity. An understanding of the mechanistic course of the formation of the 1,2-disubstituted benzimidazoles has been outlined that would rationalise the origin of selectivity control under the set experimental parameters.

Selectivity control during the solid supported protic acids catalysed synthesis of 1,2-disubstituted benzimidazoles and mechanistic insight to rationalize selectivity

Sanjeev K. Garg

Papers

Progress in COX-2 Inhibitors: A Journey So Far

2-(2-Arylphenyl)benzoxazole As a Novel Anti-Inflammatory Scaffold: Synthesis and Biological Evaluation.

Copper(II) tetrafluoroborate as a novel and highly efficient catalyst for Michael addition of mercaptans to α,β-unsaturated carbonyl compounds

α-Aminophosphonates as novel anti-leishmanial chemotypes: synthesis, biological evaluation, and CoMFA studies

Selectivity control during the solid supported protic acids catalysed synthesis of 1,2-disubstituted benzimidazoles and mechanistic insight to rationalize selectivity