Mini Reviews in Medicinal Chemistry - Online First

Inflammation is a key contributor to the pathophysiology of various chronic diseases, including cancer, arthritis, cardiovascular disorders, chronic wounds, and gastrointestinal conditions, many of which rank among the leading causes of mortality worldwide, according to the WHO. The prevalence of chronic inflammation-related diseases is projected to rise steadily over the next 30 years, with an estimated three out of five individuals dying daily as a result of such conditions. Consequently, there is a growing demand for the discovery of novel anti-inflammatory agents. Cyclooxygenases play a pivotal role in inflammatory processes, being responsible for the synthesis of prostaglandins.

COX-1 is constitutively expressed and primarily associated with “housekeeping” physiological functions, whereas COX-2 is an inducible isoform involved in inflammatory responses. Due to its role in inflammation and relatively favorable gastric safety profile compared to traditional NSAIDs, COX-2 inhibitors have emerged as a significant therapeutic target for inflammation-related disorders. However, the increased risk of stroke and heart attack associated with COX-2 inhibitors has led to the withdrawal of several approved COX-2-targeting drugs from the market. Consequently, the development of new COX-2 inhibitors with potent efficacy and minimal cardiovascular side effects is of critical importance. This review explores a range of oxygen- and nitrogen-containing heterocycles as potential anti-inflammatory agents, emphasizing their COX-2 inhibitory activity, structure–activity relationships, and interactions within the COX-2 active site, as reported in recent studies. The article covers research findings published from 2019 through the first quarter of 2025.

Millions of people worldwide are affected by neurodegenerative disorders (NDs), which include a broad range of clinical ailments that affect the brain or peripheral nervous system, including Alzheimer’s disease (AD), Parkinson's disease (PD), Huntington's disease, etc. Neuronal cell death in NDs is often linked to oxidative stress; thus, antioxidant treatment can combat oxidative cell damage, and this strategy has been studied in neurodegenerative processes. Over the past 10 years, we have witnessed intense research activity on the biological potential of human monoamine oxidase (hMAO) inhibitors that have been associated with the prevention of oxidative stress and inflammation. These inhibitors have emerged as promising therapeutic agents, especially in the treatment of neurodegenerative diseases (NDs), where their core activity may help mitigate disease progression. An overview of the current state of numerous scaffolds, such as chromones, coumarins, chalcones, propargylamines, benzothiazoles, aminoisoquinolines, and the natural compounds, including ferulic acid, resveratrol, and chrysin, which combine antioxidant capability and hMAO inhibition is given in this review, with particular attention given to each scaffold's mechanism of action and structure-activity relationships (SARs), which are thoroughly discussed. Focusing on the dual mechanism of action, combining inhibition and antioxidant properties, as a potential therapy for neurodegenerative diseases, we have reviewed the different chemical classes of multi-target-directed ligand (MTDL) inhibitors developed within this framework. Other central nervous system (CNS)-related enzymes, such as cholinesterases, carbonic anhydrases, and BACE-1, have also been explored as targets in the MTDL strategy. By understanding their biological activity, medicinal chemists can better comprehend biological activity and recommend more effective and specific ND treatments.

Carbamate has been extensively used as a scaffold in the recent era of drug discovery and is a common structural motif of many approved drugs. The carbamate moiety's unique amide-ester hybrid (-O-CO-NH-) feature offers the designing of specific drug-target interactions. Despite the discovery of numerous carbamate derivatives that act on the endocannabinoid system (ECS), the development of clinically effective carbamates remains a challenge. In this review, we highlight the therapeutic potential of carbamate inhibitors of endocannabinoid degrading enzymes as a breakthrough in discovering neurotherapeutic drugs. We discuss the design strategies and medicinal chemistry aspects involved in developing carbamate-based molecular architectures that modulate the endocannabinoid signaling pathway by interfering with fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and α/β-Hydrolase domain-containing 6 (ABHD6). Additionally, we highlight the dual activity profile of carbamates against FAAH and MAGL, FAAH and cholinesterase, and FAAH and TRPV1 channels. Furthermore, we illustrate the pharmacophores of O-functionalized carbamates and N-cyclic carbamates that are crucial for FAAH and MAGL inhibitory activities, respectively.