Mini Reviews in Medicinal Chemistry - Online First

Polysaccharide-based iron oxide nanoparticles, particularly PSC-iron oxide nanoparticles, have emerged as promising agents for brain cancer diagnosis and therapy. Originally approved for anemia treatment, PSC-iron oxide nanoparticles leverage extended circulation time, biocompatibility, and MRI contrast capabilities to serve dual diagnostic and therapeutic roles. This review highlights its application in brain tumor management, focusing on enhanced MRI visualization of tumor vascularization and macrophage activity compared to gadolinium-based agents, which improve tumor delineation and treatment monitoring. Additionally, PSC-iron oxide nanoparticles exhibit immune-modulating properties that promote anti-tumor macrophage responses. Preclinical evidence supports the synergistic effects of this approach with existing therapies and its potential in hyperthermia applications. Challenges in clinical translation, including dosage optimization and safety, require further investigation. This review highlights the potential of PSC-iron oxide nanoparticles in current findings to advance precision medicine or nanomedicine approaches for brain tumors.

Psoriasis is a chronic inflammatory skin disorder affecting 2-3% of the global population. It is increasingly recognized for its systemic comorbidities, especially cardiovascular diseases (CVDs). Notably, severe psoriasis independently increases cardiovascular disease (CVD) risk. This elevation occurs beyond conventional risk factors, such as hypertension and diabetes. It suggests that shared inflammatory pathways underlie the association between severe psoriasis and atherosclerotic conditions, like coronary artery disease (CAD). Atherosclerosis, characterized by lipid-laden plaque formation in arterial walls, remains a leading contributor to CVD-related morbidity and mortality. Emerging evidence underscores the interplay of inflammatory cell heterogeneity and immune dysregulation in its pathogenesis, mirroring mechanisms observed in psoriasis. The overlapping systemic inflammation and immune dysfunction in both diseases suggest potential therapeutic synergies. CD4⁺ regulatory T cells (Tregs), pivotal immunosuppressive modulators, have shown promise in mitigating autoimmune responses, yet their therapeutic exploitation in psoriasis-atherosclerosis comorbidity remains underexplored. This review summarizes current insights into Tregs' roles in psoriasis and atherosclerosis, emphasizing their dual regulatory functions; in psoriasis, Treg dysfunction exacerbates interleukin-17 (IL-17)/23-driven keratinocyte hyperproliferation, while in atherosclerosis, impaired Treg activity permits pro-inflammatory cytokine cascades and foam cell formation. We, herein, highlight emerging approaches to enhance Treg stability and function, such as nanotechnology-based targeting antibodies and traditional Chinese medicine (TCM). By delineating Treg-centric mechanisms across both diseases, this review proposes a paradigm shift toward immunomodulatory therapies addressing psoriasis-atherosclerosis crosstalk, offering novel strategies to alleviate systemic inflammation and cardiovascular burden in psoriatic patients. Further research into Treg heterogeneity and microenvironmental cues may unlock precision therapies for this comorbid axis.

As the main fermentation product of Aspergillus fumigatus (A. fumigatus), fumagillin is directly related to the gene of A. fumigatus and exhibits a variety of biological activities. However, its clinical application is limited by low yield and toxicity. It is of great significance to improve the yield and safety of fumagillin using A. fumigatus. Currently, research on fumagillin at home and abroad primarily focuses on a single direction and lacks a systematic review of its biosynthesis, structure-activity relationship, and strain modification technology, as well as a comprehensive theoretical framework. This study systematically reviews the biosynthesis mechanism, activity characteristics, and targeted strain modification technology of fumagillin, providing theoretical support for breakthroughs in production, toxicity regulation, and clinical transformation of fumagillin.

The primary feature of Parkinson's disease (PD), a progressive neurodegenerative disease that results in both motor and non-motor dysfunctions, is the degeneration of dopaminergic neurons in the substantia nigra. In recent years, indole-based compounds have emerged as promising candidates for developing novel treatments for Parkinson's disease due to their diverse pharmacological properties. Among the significant pathogenic targets against which indole derivatives exhibit potent activity are monoamine oxidase (MAO), NMDA receptors, oxidative stress, and neuroinflammation. This review provides an in-depth analysis of synthetic indole derivatives as potential therapeutic agents for Parkinson’s disease. We explore how these compounds may reduce the pathology associated with Parkinson's disease, identify molecular targets, and analyze the relationships between their structure and activity. We also discuss recent advances in computational and medicinal chemistry that aim to enhance indole structures. Potential challenges and upcoming prospects for the therapeutic application of indole-based therapies are also considered in the review. The ultimate objective of this study is to elucidate the potential applications of synthetic indole derivatives in the development of innovative therapies for Parkinson's disease.

Glucose control remains the primary target in the treatment of both Type 1 and Type 2 diabetes. Glycemia plays a major role in preventing both macrovascular and microvascular complications. Some diabetes medications can also affect body weight. This article describes the various categories of antidiabetic medications and their effects on weight and HbA1c (Hemoglobin A1c) levels in patients with Type 1 and Type 2 diabetes. The weight and glycemic control effects of antidiabetic drugs approved for the management of weight loss are also reviewed in this article. Several types of medications are available that work through different mechanisms to help lower blood glucose levels. The risk of weight gain or weight loss depends on both the medication used and lifestyle factors such as diet and exercise. A reduction in glycosuria is the primary reason for weight gain; however, reducing calorie intake can help minimize this effect. Nevertheless, due to limited access to adequate nutrition education, many people are unable to complement changes in medical therapy with necessary lifestyle adjustments. Some diabetes medications can cause weight loss by getting rid of extra glucose from the body or lowering the amount of glucose our liver makes. Some diabetes medications have little to no effect on weight for most people, and healthcare professionals sometimes refer to these as “weight-neutral” diabetes medications. Certain medications promote weight loss in addition to exerting extra-glycemic and extra-pancreatic effects, which positively impact cardiovascular risk by reducing both mortality and morbidity. Verification and further explanation of the actual mechanisms underlying the life-prolonging effects of these antidiabetic medications are still needed. Their effects on biomarkers that mimic calorie restriction in patients also require confirmation. Additional research should be conducted to clarify the details of lifespan extension. Furthermore, when herbs are administered alongside antidiabetic medicines, they may alter the pharmacokinetic and pharmacodynamic properties of the drugs, rendering them less effective or potentiating their activity and producing adverse effects.

The mounting threat of antimicrobial resistance has intensified the global search for novel antibacterial agents, and chalcones - the aromatic ketones characterized by an α, β-unsaturated carbonyl system has emerged as promising scaffolds against the threat of antimicrobial resistance. This review presents a detailed exploration of chalcones as potent antibacterial agents, emphasizing their structural versatility, mechanisms of action, and therapeutic potential. With a modular backbone that supports diverse substitutions and heterocyclic extensions, chalcones can be easily synthesized and chemically optimized to target a broad spectrum of bacterial pathogens, including multidrug-resistant strains such as MRSA and VRE. Mechanistically, chalcones exert antibacterial effects through multiple pathways, like disrupting bacterial membranes, inhibiting cell wall biosynthesis, interfering with DNA replication via DNA gyrase and topoisomerase IV, and suppressing protein synthesis. Their amphipathic nature and ability to bind critical bacterial enzymes offer an advantage in circumventing classical resistance mechanisms. Structure-activity relationships and computational studies have further elucidated the influence of electron-donating and electron-withdrawing groups, positional isomerism, and heterocyclic integration on antibacterial potency. A review of recent literature underlines the efficacy of chalcone derivatives against Gram-positive and Gram-negative strains, with many compounds demonstrating promising activity, such as compound 85 with MIC 3.4 nM against Ciprofloxacin with MIC 4.7 nM. The review also highlights advancements in green synthesis, QSAR modeling, and molecular docking, which collectively facilitate the rational design of next-generation chalcone-based antibacterials. Altogether, chalcones represent a structurally simple yet biologically robust class of compounds, offering significant promise as adaptable and effective agents in the evolving landscape of antimicrobial therapy.

Ruthenium complexes stand out as an excellent alternative in the field of organometallic chemistry with applications in various areas. Recently, in cardiovascular pharmacology, there has been a growing interest in investigating complexes that modulate the Nitric Oxide (NO) pathway without necessarily and directly donating NO. NO has a proven vasodilatory and cardioprotective effect, and it is known that reduced levels are associated with an increased risk of CardioVascular Diseases (CVD). Studies suggest that ruthenium complexes significantly contribute to the treatment of CVD pathophysiology through different pharmacological mechanisms, including the precise delivery of carbon monoxide (CO) to the molecular target, the release of nitric oxide species under visible and invisible (UV) light, the ability to stimulate the activation of soluble Guanylate Cyclase (sGC) enzyme, participation in the opening of potassium channels, and reduction of cytoplasmic calcium levels. This study aims to conduct a narrative review of the cardiovascular effects of ruthenium complexes, focusing on hypertension and myocardial injury, and demonstrate that metal complexes acting on the NO pathway may have promising targets for the development of therapeutic strategies in CVD treatment.

Cardiovascular diseases are the leading cause of death worldwide. Despite the development of a wide variety of drugs, treatment regimens do not seem to be able to prevent the progression of these pathologies. In recent years, the study of epigenetic mechanisms has led to the discovery of new targets that may facilitate the search for therapeutic alternatives. Furthermore, it has been demonstrated that the onset of cardiovascular diseases is associated with changes in DNA methylation status and altered histone modification patterns. Therefore, the use of natural and synthetic inhibitors of epigenetic modulators, such as DNA methyltransferases (DNMTs), is likely to constitute a new approach in the therapy of cardiovascular diseases. In this review article, we discuss the mechanisms of action of inhibitors of epigenetic modulators and their applications in the treatment of cardiovascular diseases.

Individuals diagnosed with inflammatory bowel disease (IBD) face a significantly heightened risk of developing colorectal cancer (CRC), primarily due to persistent intestinal inflammation that fosters neoplastic transformations across the colon. This narrative review delves into the potential of certain fruits, such as black raspberries, Amazonian açaí, apples, grapes, cocoa, Ziziphus jujuba, and Moringa oleifera, in mitigating IBD-induced CRC. Preclinical studies indicate that these fruits possess anti-inflammatory and antioxidant properties that may disrupt carcinogenic pathways. Notably, black raspberries have demonstrated the ability to modulate epigenetic markers by demethylating tumor suppressor genes and inhibiting DNA methyltransferases (DNMT), like DNMT1 and DNMT3B. This epigenetic modulation influences the Wnt signaling pathway, crucial in CRC development, and affects cellular processes, such as proliferation, apoptosis, and angiogenesis. Animal models further support these findings, showing that black raspberries can suppress β-catenin signaling, reduce chronic inflammation, and decrease tumor incidence. This comprehensive analysis underscores the promising role of specific fruits in CRC prevention among IBD patients and highlights the need for further research to translate these findings into clinical applications, potentially benefiting both public health and the nutraceutical industry.

Breast cancer is a heterogeneous disease consisting of several molecular subtypes, such as Hormone Receptor-positive (HR+), Human Epidermal Growth Factor Receptor 2-positive (HER2+), and Triple-Negative Breast Cancer (TNBC). Although a lot of success has been realized in targeted agents, there still remain significant problems, including resistance to drugs, toxicity related to treatment, and few therapeutic possibilities for aggressive subtypes. Confronting such limitations requires complementary treatment approaches with better efficacy and safety profiles. Phytoconstituents from natural sources have emerged as potential therapeutic agents due to their multitargeting activity, good safety profile, and capacity to evade drug resistance. These bioactive molecules, such as flavonoids, alkaloids, terpenoids, and saponins, possess various mechanisms of action, including modulation of cell cycle regulators, induction of apoptosis, inhibition of angiogenesis, suppression of metastasis, and regulation of critical oncogenic signaling pathways. Their interference with several cancer pathways gives them a holistic strategy for breast cancer therapy. This review offers an in-depth examination of new phytoconstituents that target the molecular basis of various subtypes of breast cancer. It also highlights their scope for integration into traditional paradigms either as monotherapy or in combination with current therapies to increase therapeutic impact with the least adverse effects. Through the clarification of their mechanisms of action and therapeutic advantages, this review promotes the ongoing pursuit of phytoconstituents as potential contenders in contemporary oncology, providing novel targets for the control of breast cancer and enhanced patient care.

Musculin antisense RNA 1 (MSC-AS1) is a long non-coding RNA (lncRNA) located on human chromosome 8q13.3-q21.11. Emerging evidence shows that MSC-AS1 is either upregulated or downregulated in 16 types of human cancers, and is associated with clinical pathological features and patient prognosis in 12 of these cancers. It is widely believed that the dysregulation of MSC-AS1 contributes to tumor cell growth, metastasis, epithelial-mesenchymal transition (EMT) progression, metabolic reprogramming, and drug resistance formation. Mechanistically, MSC-AS1 can act as a competing endogenous RNA (ceRNA) by sponging 14 miRNAs to affect the expression of downstream mRNAs, or it may directly interact with proteins, both of which contribute to the activation of the PI3K/AKT and Wnt/β-catenin signaling pathways. Our review study suggests that MSC-AS1 is a potential cancer biomarker and therapeutic target. In summary, we have explained the research on MSC-AS1 related to cancer treatment, its expression patterns, functional characteristics, and molecular mechanisms in malignant tumors. We have further emphasized its significance in clinical prognosis and therapeutic applications.

Quinoxalines are a versatile class of nitrogen-containing heterocyclic compounds that have been extensively studied for their diverse pharmacological properties. Recently, interest has grown in exploring quinoxaline derivatives for applications in oral health, driven by their unique mechanisms of action and potential to address major challenges in dental medicine. This review comprehensively examines the recent progress in the development of quinoxaline-based compounds targeting oral pathogens responsible for dental caries, periodontitis, and other biofilm-associated diseases. Beyond their antimicrobial effects, quinoxalines also exhibit anti-inflammatory properties by modulating key molecular pathways implicated in periodontal inflammation, thereby offering a dual therapeutic potential. Moreover, their incorporation as functional additives in restorative dental materials is emerging, aiming to enhance antimicrobial efficacy and improve material performance. Despite promising in vitro and in vivo data, several critical barriers must be overcome before clinical translation can be realized. These include ensuring biocompatibility with oral tissues, achieving formulation stability under the dynamic conditions within the oral environment, and optimizing delivery systems to ensure targeted, sustained release at the site of action. This review highlights current strategies to address these challenges and proposes directions for future research, including advanced formulation technologies and comprehensive preclinical evaluations. Ultimately, quinoxaline derivatives hold significant promise as multifunctional agents capable of integrating antimicrobial, anti-inflammatory, and biomaterial-enhancing properties to improve oral health outcomes. This synthesis of current knowledge supports continued investigation into quinoxalines as novel therapeutics and functional components for dental care.

Medical diagnostics, environmental monitoring, and food safety are key domains being transformed by the ongoing revolution in optical biosensors. These light sensors are highly sensitive and specific for detecting specific biological interactions, allowing for real-time, label-free detection. Biorecognition elements (such as enzymes, antibodies, or nucleic acids), following interaction with the target analyte, generate optical signals based on the same key principles as optical biosensors. Surface plasmon resonance (SPR), fluorescence-based sensors, and fiber optic sensors offer a wide range of biosensors capable of detecting a broad spectrum of biological and chemical agents at trace concentrations. Diagnostic capability has become efficient and rapid with advances in nanotechnology and microelectronics, particularly in nanopores. Monitoring of cardiovascular health using wearable optical biosensors, such as photoplethysmography (PPG), is a non-invasive method. It has also been recently improved to better track heart rate and blood pressure, as well as evaluate mental and vascular health. Wearable optical biosensors support technologies, such as continuous monitoring and early detection of anomalies, which help in personalized healthcare. Optical biosensors are particularly suitable for detecting pathogens, biomarkers, and pollutants in clinical settings, as well as for environmental monitoring and food safety assessments. These applications range from biopharmaceuticals to biotechnology and personalized care, which are used to monitor diseases, discover drugs, and detect pathogens. Despite progress, matrix interference with the sample matrix, sensor stability, and miniaturization remain challenges to be overcome. However, with future progress in materials science, nanotechnology, and increased integration with the Internet of Things (IoT), the potential for optical biosensors will continue to rise as portable, cost-effective, real-time data-analyzing diagnostic tools that expand accessibility to those in underserved regions. Developed using optical and electrochemical approaches, the biosensors reviewed in this article are discussed in terms of their principles, types, applications, and prospects, including their roles in healthcare and environmental sectors.

The urinary tract (UT) was once considered sterile, but now it is known to host a diverse community of microorganisms, known as the urinary microbiome. The collective microbiota is made up of bacteria, fungi, and viruses, necessary for maintaining UT health. This review aims to synthesize current knowledge on the urinary microbiome and clarify its emerging role as a key modulator in both health and a wide spectrum of UT disorders. Dysbiosis within this microbial community has been linked to conditions such as urinary tract infections (UTIs), interstitial cystitis/bladder pain syndrome (IC/BPS), urinary incontinence, urolithiasis, benign prostatic hyperplasia (BPH), and even urinary tract malignancies. Advances in methodologies, such as expanded quantitative urine culture and metagenomics, have provided valuable insights into microbial variability influenced by factors like age, sex, and disease conditions. Additionally, this review explores the therapeutic potential of probiotics and bacteriophages, as well as the association of urinary microbiota with autoimmune and inflammatory conditions. Special emphasis is placed on translational relevance, including emerging microbiome-targeted therapies and personalized interventions for UTIs. Ethical considerations allied with UT microbiome research, such as data privacy, informed consent, and equitable access to emerging therapies, are also discussed. Despite substantial progress, challenges such as methodological heterogeneity, a lack of longitudinal data, and unresolved causal relationships persist. The study concludes by identifying key knowledge gaps and proposing future directions for multidisciplinary research to advance therapeutic innovation in urological health.

aThe growing prevalence of multidrug resistance and its detrimental effects pose a significant threat to public health, which is one reason for the current interest in the introduction of novel agents. To combat this adverse effect and drug resistance, numerous drugs have been developed over time, and their safety is still being evaluated; derivatives or medications based on the carbazole moiety are one of the key contributors. Therefore, this review explores carbazole-based derivatives as possible drugs to treat Alzheimer's, diabetes, inflammation, cancer, and many more, along with their synthetic schemes, SARs, and activity. Some of the carbazole-based drugs available in the market and under clinical trials are also tabulated. By integrating this insight, describe how these compounds are being reinvented as targeted therapeutic agents. This comprehensive analysis is designed to guide researchers in developing next-generation drugs to address various challenges and leverage the unique pharmacological properties of carbazole-derived drugs.

Arthritis has become a global public health issue due to its diverse risk factors and high prevalence. Therefore, there is a demand for more effective drugs to improve these situations. Triterpenoids have attracted the interest of researchers because of their broad spectrum of biological activities and pharmacological effects. The aim of this review is to provide an updated overview of the potential of triterpenoids and of their derivatives as therapeutic agents against Rheumatoid Arthritis (RA) and Osteoarthritis (OA), based on their anti-inflammatory and immunomodulatory properties. This review discusses the chemical and pharmacological properties of triterpenoids and their derivatives, focusing on the different mechanisms by which this class of compounds achieves therapeutic benefits in arthritis. The conclusions indicate that triterpenoids and their derivatives have a favorable potential therapeutic effect on arthritis.

Recent trends have shown the development of various medicinally important compounds that specifically target B-cell receptor (BCR) pathways at various segments that have a major role in Bruton’s tyrosine kinase (BTK) receptor, which belongs to the family of kinases. These kinases are usually situated close to the cell membrane due to which they participate in upstream processing of BCR signalling. Various molecules have been potentialized to target these signalling pathways of these kinase receptors in order to achieve a pharmacological effect. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of multiple diseases. BTK inhibitors work by regulating B-cell receptor signalling along with inflammatory pathways and immune cell interactions, offering more advanced treatment options compared to traditional therapies. In addition to BTK inhibitors, an extensive knowledge of the pharmacological mechanisms underlying the blockage of these receptors is necessary in order to more accurately forecast when and where a patient could need combination therapy or just one medication. Efforts have been made to facilitate translational discoveries, drug re-purposing concepts, and further development of precision medicine products. This thorough literature study has focused on studies published until June 2025.

Intracellular calcium (Ca²⁺) levels are critical in maintaining cellular activities and are tightly regulated. Neuronal degeneration and regeneration rely on calcium-binding proteins. Calmodulin (CaM) is a calcium sensor and the primary regulator of receptors and ion channels that maintain calcium homeostasis. The calmodulin binding domains are present in proteins that serve as risk factors and biomarkers associated with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and other neurodegenerative diseases, suggesting calmodulin ligands as emerging therapeutic targets for treatment. Inhibiting CaM to develop new therapies has drawbacks, as CaM is a ubiquitous molecule involved in many regulatory pathways. Recently, new strategies for disrupting CaM interactions with its targets have shown promising approaches to treatment.

The structures of human CaM, its binding proteins, and inhibitors are well studied, with particular emphasis on the conservation of CaM amino acid sequences and the ability to bind protein fragments of high sequence variability, which exhibit common characteristics of amphipathic helices carrying basic amino acids.

In this review, we discuss structural characteristics of CaM and its ligands in the context of transcriptional regulation. Specific binding of CaM to (1) basic region/helix-loop-helix/leucine zipper and (2) helix-turn-helix high mobility group box containing Sox families of transcription factors highlights common features of CaM binding sequences, which suggest their regulatory functions. We describe key proteins involved in neurodegeneration and transcription factors subject to calmodulin regulation that are candidates for the development of new approaches to treating neuronal diseases.

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.