Sulfonylureas (SUs) have been used in the treatment of type 2 diabetes since the 1950s, yet growing evidence shows that many members of this class also exert biologically relevant off-target effects that may be exploited in oncology and other therapeutic contexts. This review provides a structured overview of the literature from 1956 to 2025, integrating preclinical studies, clinical and epidemiological data, pharmacovigilance signals, and patent activity. To facilitate comparison across compounds, the available evidence is organized into drug-specific mechanistic maps rather than treated as a uniform class effect. Across the literature, SUs have been linked to modulation of KATP channels, ABC transporters involved in multidrug resistance, gap-junction communication, redox balance, mitochondrial function, inflammatory signaling, and DNA damage-related pathways. However, these activities differ markedly between individual agents. Glibenclamide emerges primarily as a chemosensitizing and transporter-modulating compound, gliclazide as a drug with antioxidant, anti-inflammatory, and DNA-protective properties, glimepiride as a promising synergistic agent with additional AKR1C3-inhibitory activity, tolbutamide as a modulator of gap-junction signaling and mitochondrial stability, and chlorpropamide derivatives as ALDH-targeting chemosensitizers. At the same time, the review highlights major translational constraints, including weak baseline cytotoxicity for most SUs, frequent exposure mismatches between experimental and clinical settings, heterogeneous safety profiles, photoreactivity, and limited commercial incentives for development, while also outlining practical strategies to address these limitations. Overall, SUs should not be viewed as a single repurposing candidate, but as a chemically related set of drugs that require indication-specific and compound-specific selection for future oncology applications.

Psychiatric disorders severely challenge the public health, but the development of new psychotropic medications cannot keep pace with clinical needs. The rapid accumulation of single-cell RNA data provides opportunities to develop new computational approaches of drug repurposing. However, there is a lack of dedicated computational tools for psychiatric disorders in this field. In this work, we developed a cell-type specific interaction based computational pipeline scPsyDrug to prioritize the drugs for psychiatric disorders. This tool integrated the single-cell transcriptomics, protein-protein interactions, drug-target interactions and psychiatric risk genes to construct cell type-specific interactions and seed genes for drug prioritization. We first evaluated the scPsyDrug performance using the publicly available single cell RNA datasets derived from the clinical patients, including Major Depressive Disorder, Schizophrenia and Parkinson's disease, in which scPsyDrug covered lots of approved drugs and clinical-trial compounds in the top recommended candidates. We next applied scPsyDrug to Zbtb18[+/-] mice, an anxiety-like mouse model, to screen the potential drugs. The scPsyDrug prioritized Forskolin and Chlorpropamide as the top candidates, while the following drug treatment demonstrated that these two compounds could respectively rescue the anxiety-like behaviors in Zbtb18[+/-] mice. We also used scPsyDrug to screen herb ingredients, and validated the efficacy of Osthole in rescuing the anxiety-like behaviors in the mouse model. Collectively, the scPsyDrug can be applied to different kinds of psychiatric disorders for drug repurposing, and we also provided experimental evidence for the potential roles of Forskolin, Chlorpropamide and Osthole in anxiety intervention.

For prehospital providers, there are several causes for the patient with altered mental status or being unconscious to include the mnemonic AEIOU TIPS for Alcohol and acidosis, Endocrine, Epilepsy, Electrolytes, Encephalopathy, Infection, Opiates, Overdose, Uremia, Underdose, Trauma (head injury and blood loss), Insulin, Poisoning, Psychosis, Stroke, Seizure, and Syncope. Hypoglycemia, or low blood glucose level, is one of the most common causes of altered mental status for patients with and without diabetes. Estimates are that 1 to 2 percent of prehospital encounters and 7% of refusals are for hypoglycemia.[1][2] Diabetes mellitus often referred to as "diabetes" or "sugar" by laypeople is the most common endocrine disorder where the body does not either produce enough insulin or has a resistance to the circulating insulin, and is characterized by high blood sugar levels over prolonged periods. The three main types of diabetes are type I (previously referred to as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset), type II (formerly referred to as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset) and gestational.[3] Insulin is an anabolic hormone produced in the beta cells of the pancreatic islets. The primary function of insulin is to regulate the metabolism of carbohydrates, protein, and fat through the absorption of glucose sugar from the blood into the liver, fat, and skeletal muscle cells. These small glucose molecules are then converted into larger molecules and stored for later usage.  Type 1 Diabetes Mellitus (T1DM) [4] This condition is commonly referred to as insulin-dependent diabetes or previously as childhood/adolescent-onset diabetes. It accounts for approximately 5% to 10% of all cases of diabetes. It can be related to the autoimmune destruction of insulin-producing beta cells in the islets of the pancreas from different causes, including genetic susceptivity, viral illness, toxins or alcohol-induced pancreatitis, or some dietary factors.  The age group affected is usually children and adolescents, but adults can develop T1DM.  As the name "insulin-dependent" implies, it requires the administration of subcutaneous insulin via intermittent injections or pump infusion. Type 2 Diabetes Mellitus (T2DM) [4] [5] This variant is commonly referred to as non-insulin diabetes or previously as adult-onset diabetes.  It accounts for approximately 90% of all cases of diabetes.  It is related to the desensitization of insulin/insulin resistance (response to insulin becomes diminished) in various tissues. Initially, there is an increase in insulin production, but this decreases over time. T2DM most commonly presents in persons older than 45 years, but it increasingly occurs in children, adolescents, and younger adults due to rising levels of obesity, physical inactivity, and energy-dense diets. Gestational Diabetes Mellitus (GDM) Hyperglycemia first detected during pregnancy is classified as gestational diabetes mellitus (GDM). Although it can occur anytime during pregnancy, GDM generally affects pregnant women during the second and third trimesters. According to the American Diabetes Association (ADA), GDM complicates 7% of all pregnancies. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future.  Types of Therapies [6] Therapy for hyperglycemia is dependant upon how much insulin the body is producing, or how well that insulin that is produced is working.  The majority of patients with T2DM will be on an oral type of medication.  Patients with T1DM will be on a combination of either long-acting insulin with short-acting as a sliding scale, intermediate-acting insulin with short-acting insulin as a sliding scale, combination premixed insulin, or be on an insulin pump. Hypoglycemia  One of the public health concerns for diabetes mellitus and unintended complications for the reduction in blood glucose levels is hypoglycemia.[1][7][8] Hypoglycemia, by definition, is a plasma glucose concentration below 70 mg/dL, with most patients not having signs or symptoms until the plasma glucose concentrations drop below 55 mg/dL.[9]  Low plasma glucose concentration that requires assistance from another individual qualifies as severe hypoglycemia, and by context, all EMS encounters fall into this category.[1][10]  There has been an increase in morbidity (poor quality of life, series falls or car accidents, dementia, and hospitalization) and mortality related to severe hypoglycemia.[1]  Based upon 2015 data from NEMSIS, prehospital activation for diabetes-related cases accounts for about 2.3% of all activations, with the primary EMS encounter being hypoglycemia.[11] Patients experiencing severe hypoglycemia or other diabetes-related concerns typically reach out for help by calling 911 who may dispatch a fire department or EMS agency depending on the jurisdiction. Care is then provided by the first on scene provider who may be an emergency medical technician (EMT) intermediate or advanced emergency medical technician (IEMT or AEMT) or paramedic. Treat and release versus transport of patients with hypoglycemia by EMS providers depends on the clinical guidelines or protocols from either the state or regional level by medical directors. It is important to understand that patients with severe hypoglycemia are at a higher risk of having complications related to the hypoglycemic state.  Villani et al. indicated that approximately 50% of patients with severe hypoglycemia required transport to the hospital, and of that group, 41.3% were admitted to the hospital.[12][13][14]  One of the first studies on the topic of treating and releasing hypoglycemic patients in the field was "Development and Evaluation of Criteria Allowing Paramedics to Treat and Release Patients Presenting with Hypoglycemia: A Retrospective Study" published in Prehospital and Disaster Medicine in 1991.   Their study design proposed five criteria that would allow for appropriate release that would not require additional treatment from prehospital providers to include: 1. The patient has a history of type 1 or type 2 diabetes. 2. Blood sugar prior to treatment is below 4.4 mmol/L or 80 mg/dL. 3. Blood sugar after treatment is equal to or greater than 4.4 mmol/L or 80 mg/dL. 4. The patient has a normal mental status within 10 minutes of treatment.  5. The patient does not have any other complicating factors that required ED evaluation to such alcohol, chest pain, dyspnea, injuries related to falls, and/or renal dialysis. A 2016 study by Rostykus et al. reviewed prehospital clinical guidelines for hypoglycemia in 185 EMS agencies in the United States.  It revealed that less than half allowed for non-transport of patients with hypoglycemia after the low plasma glucose level was corrected.[15] A study by Moffet et al. looked at hypoglycemic patients treated by EMS in Alameda County from 2013 to 2015 and found that the transport rate was 13.5%. The demographic trends for those non-transported patients were adult patients < 60 years of age, males, finger stick blood glucose levels > 60 mg/dl, and EMS arrival times between 1800 and 0600.[1]

Chlorpropamide is no longer marketed in the United States. Limited data indicate that amounts of chlorpropamide in breastmilk are unlikely to affect a breastfed infant. Short-acting drugs are generally preferred while breastfeeding a neonate to avoid drug accumulation. Monitor breastfed infants for signs of hypoglycemia such as jitteriness, excessive sleepiness, poor feeding, seizures cyanosis, apnea, or hypothermia. If there is concern, monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with hypoglycemic agents.[1,2]

Microscale affinity chromatography (μAC) was used with covalent protein immobilization and zonal elution to quickly screen and compare binding by several sulfonylurea-based antidiabetic drugs with human serum albumin (HSA) and forms of this protein containing advanced glycation end-products (AGEs). The HSA was modified with glyoxal or methylglyoxal and examined for its binding to the following drugs: acetohexamide, chlorpropamide, gliclazide, glipizide, tolbutamide, and tolazamide. The HSA was coupled by the Schiff base method onto HPLC-grade silica, which was then placed into 10 mm × 2.1 mm i.d. affinity microcolumns. These microcolumns each contained ∼1 mg HSA and could be used for over 450-500 sample injections. The drugs were injected onto these microcolumns at 37 °C and pH 7.4, giving retention data at 0.50 mL/min within a few minutes (e.g., less than 5 min for normal HSA). The overall binding constants obtained for normal and AGE-modified HSA were consistent with the literature, showing a strong correlation with prior values estimated when using immunoaffinity chromatography and the biospecific adsorption of HSA. These results indicated that μAC combined with zonal elution screening and Schiff base immobilization was an effective approach for studying the interactions of sulfonylurea drugs with HSA and modified forms of this protein. This approach can be extended to other proteins and drug-protein interactions, as could be used for fundamental research or aid in the development of new treatments through personalized medicine.

The antidiabetic drug chlorpropamide [1-(4-chlorophenyl)sulfonyl-3-propylurea, CPA] has one of the highest numbers of reported polymorphs, making it an excellent model system for studying structural responses to pressure or temperature. The densest polymorph, δ-CPA, was probed by single-crystal X-ray diffraction at both laboratory and synchrotron facilities. A new high-pressure phase with tripled cell parameter b as compared with the ambient pressure phase was discovered. High-brilliance synchrotron sources and fast data collection strategies allowed us to also detect the formation of the intermediate incommensurately modulated phase at 2.37 (5) GPa. The experiments revealed the effect of the pressure-increasing protocol on the structure evolution on hydrostatic compression. The importance and necessity of conducting both laboratory and synchrotron experiments for the same compound when studying solid-state transformations is illustrated. The opportunities provided by synchrotron sources for studying phase transformations are discussed, together with specific characteristics of synchrotron experiments that should not be overlooked.

Triptolide (TP), as a principal bioactive compound derived from Tripterygium wilfordii Hook. f., exhibits significant anti-tumor, anti-inflammatory, and immunomodulatory properties. However, the serious adverse reactions and hepatotoxicity of TP limit its clinical application. Therefore, in this study, an intraperitoneal injection was employed to establish a TP-induced hepatotoxicity model, characterized by elevated levels of transaminases (AST and ALT) and metabolic disorders. The administration of the JNK inhibitor SP600125 effectively mitigated the elevated transaminases and inflammation induced by TP. The resistance of SP600125 to metabolic disturbances induced by TP was contingent upon Fxr, as demonstrated through the use of Fxr knockout mice. Supplementation of GW4064 restored the concentrations of bile acids, long-chain fatty acids, and carnitine disrupted by TP. Transcriptomic data suggested that G0s2 was one of the genes most severely disrupted by TP, and the ameliorative effects of SP600125 and GW4064 were accompanied by the upregulation of G0s2. The expression of G0s2 was disrupted by siRNA in vitro, thereby intensifying the cytotoxicity of TP. A comparative analysis of the impact of TP on the G0s2 gene in two mouse models revealed that a smaller reduction in wild-type mice compared to Fxr[-/-] mice, indicating that Fxr mitigates the inhibitory effect of TP on G0s2. The aberrant JNK/Fxr/G0s2 signaling plays a key role in TP-induced hepatotoxicity. Targeting Fxr might be a potential strategy for alleviating the liver toxicity of TP.

Acetylcholinesterase (AChE) has emerged as an important drug target for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Recent experimental studies indicate that certain antidiabetic drugs can be repurposed as potent AChE inhibitors. Enzymatic kinetic assays suggest that the antidiabetic drug chlorpropamide (CPM) acts as a noncompetitive inhibitor, but the mechanism of action and the binding site(s) of interaction with AChE are not known. In this work, we have carried out molecular dynamics (MD) simulations to discover a new allosteric site in addition to the known peripheral anionic site (PAS) as a potential binding site of this noncompetitive inhibitor. We show that the conformational ensemble of the catalytic triad, particularly the HIS447, undergoes a significant population shift on ligand binding that is responsible for deactivation of the enzyme. We also elucidate the pathway of the allosteric signaling in terms of locally correlated domains of the inter-residue interaction network. Thus, our work identifies a new allosteric site for AChE inhibition and eludiates the underlying mechanistic principles. These results would be useful for the rational design of new noncompetitive inhibitors for AChE.

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450's metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug-processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes. SIGNIFICANCE STATEMENT: This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of cytochrome P450 probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the present study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, combined here with the bile acid profile and histopathological analysis.

A metal-free process has been developed for the sustainable synthesis of medicinally important sulfonylureas in one pot via the direct reaction of sulfonamides with amides in green solvent (DMC). The reaction proceeded efficiently at room temperature, and the products were obtained in good to excellent yields. The use of readily accessible, inexpensive, and environmentally benign starting materials and reagents, metal-free mild reaction conditions, wide substrate scope, tolerance to air and moisture, operational simplicity, and good atom economy are the salient features of this reaction protocol. Gram-scale synthesis of antidiabetic drugs tolbutamide and chlorpropamide in excellent yields further revealed the practical utility of this procedure. Additionally, the synthetic value of this straightforward method is showcased by the late-stage modification of drug molecules, including drug-drug conjugation with good yields. Preliminary mechanistic studies indicated the in situ generation of an isocyanate intermediate, which further reacts with sulfonamide to form sulfonylurea. As compared to other related methods reported for sulfonylurea synthesis, the current method obviates the requirement of traditional multistep protocols involving isolation of hazardous isocyanates and avoids the use of toxic phosgene.

The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of "new conformational isomers" for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

A rapid and simple method to measure oral hypoglycemic agents is essential in the evaluation of a patient with spontaneous hypoglycemia. As a result, a robust high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the qualitative detection of first-generation sulfonylureas (e.g., chlorpropamide, tolazamide, and tolbutamide), second-generation sulfonylureas (e.g., glimepiride, glipizide, and glyburide), meglitinides (e.g., repaglinide, nateglinide), and thiazolidinediones (e.g., rosiglitazone and pioglitazone). HPLC involved a C8 column and MS/MS was used in electrospray ionization (ESI) positive mode. Identification of all compounds was made using various multiple-reaction monitoring (MRMs). Isotopic labeled chlorpropamide-d4, glimepiride-d5, glyburide-d11, nateglinide-d5, repaglinide-ethyl-d5, rosiglitazone-d3, and zomepirac were used as the internal standards. The cutoffs for each drug were as follows: chlorpropamide 100 ng/mL, tolazamide 50 ng/mL, tolbutamide 20 ng/mL, glimepiride 20 ng/mL, glipizide 5 ng/mL, glyburide 5 ng/mL, repaglinide 5 ng/mL, rosiglitazone 20 ng/mL, pioglitazone 20 ng/mL, and nateglinide 5 ng/mL.

The search for solid solutions of class-two insulin secretagogues, tolbutamide and chlorpropamide, reveals a rare case of monotropic polymorphism for the mixed crystals. At any stoichiometry, two crystal forms are isolated that are kinetically stable at room temperature from a few months to over a year. Dissolution tests certify the solubility advantage of the solid solutions over the pure drugs as well as their physical mixture, suggesting a potential application as a highly soluble co-drug formulation.