Acetohexamide is no longer marketed in the United States. Because no information is available on the use of acetohexamide during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. 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.

Drug repurposing represents a promising approach towards drug discovery that has the potential to improve patient outcomes and address unmet medical needs. This study attempted to repurpose existing sulfonamide drugs in search of novel anticancer drugs because of their effectiveness in treating bacterial infections. A search was made in DrugBank for Sulfonamide, and 25 drugs with functional groups like SH, OSO, CS, and -S- were chosen for our study. The drug properties, such as dipole moment, volume, polarisability, highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), and electrostatic potential map, were analysed through a quantum mechanical approach at different functionals: M062X, M06HF, and B3LYP with basis sets (6-31 +G*, LANL2DZ). The electrostatic potential map was analyzed to determine the magnitude, size, and distribution of the electron cloud surrounding the sulfur atoms. Analysis of NBO (Natural Bond Orbital) and NCI (Non-Covalent Interaction) plots confirmed the presence of intramolecular hydrogen bonding in the sulfonamide drugs. Furthermore, the frontier molecular orbitals (HOMO and LUMO) and the band gap were thoroughly examined for all drugs to identify the best electron acceptors and donors. Docking analysis was performed to have a lock-and-key model of 25 sulfonamide drugs with the most promising cancer-targeted protein (1ZZ1): histone deacetylases (HDACs). The best drug orientation (optimal position) was discussed and compared with the control ligand SHH based on the analysis of binding affinity and root mean square deviation (RMSD). Binding affinity of control ligand SHH is -8.1 kcal/mol for the 2nd pose, which matches exactly with 1ZZ1 SHH ligand. The drugs Tolazamide, Fezolinetant, Ensulizole, Taurolidine, Acetohexamide, Isoxicam, Sulfamethizole, Sulfamethoxazole, Sulfapyridine, Sulfaphenazole, and Dodecyl sulphate were observed to exhibit high molecular volume, polarizability, dipole moment and significant HOMO, LUMO values, which are recommended for further quantum mechanical calculations. The findings of this study will be essential for evaluating the properties of sulfonamide drugs from a drugbank using a variety of analyses in order to repurpose them as novel anticancer drugs. Quantum mechanical calculations will be performed on the optimal docking poses in future work. Keywords: Sulfonamide drugs, Docking, Histone deacetylases, Lipinsk's rule, Binding affinity.

Diabetes mellitus affects over 500 million people globally and is expected to rise significantly in the coming decades. Existing antidiabetic drugs, including α-glucosidase and α-amylase inhibitors, often exhibit side effects and limited efficacy, prompting the search for safer alternatives. Hydrazone derivatives have shown promising antidiabetic activity due to their structural diversity and enzyme-targeting potential. In this study, 10 novel hydrazone compounds were synthesized and evaluated for their inhibitory effects against α-amylase and α-glucosidase. Compounds 8 and 10 showed the highest dual inhibition: compound 8 with IC50 = 30.21 ± 0.16 μM (α-amylase) and 38.06 ± 0.80 μM (α-glucosidase); compound 10 with IC50 = 34.49 ± 0.37 and 40.44 ± 0.23 μM, respectively. Cytotoxicity on HEK293 cells via MTT assay revealed IC50 values of 61.04 μM (compound 7) and 69.25 μM (compound 9), while other compounds and acarbose were nontoxic up to 100 μM. In silico drug-likeness analysis showed that 80% of the compounds complied with Lipinski's rules, with topological polar surface area (TPSA) values ranging between 63 and 112 Å2. Gastrointestinal absorption was high for 7 out of 10 compounds; none showed blood-brain barrier permeability. Molecular docking confirmed strong binding interactions of compounds 8 and 10 with both enzymes' active sites. These findings highlight hydrazone scaffolds as potent and safe candidates for further antidiabetic drug development.

Heart failure (HF) is a severe cardiovascular disease often worsened by respiratory infections like influenza, COVID-19, and community-acquired pneumonia (CAP). This study aims to uncover the molecular commonalities among these respiratory diseases and their impact on HF, identifying key mediating genes. By performing differential expression analysis on GEO database data, we found 51 common molecules of three respiratory diseases. The gene module of HF was identified by weighted gene co-expression network analysis, and 10 characteristic genes of respiratory diseases that aggravate HF were obtained. GO and KEGG enrichment analysis showed that these genes were mainly involved in innate immune response, inflammation and coagulation pathways. By using three machine learning algorithms, LASSO, RF and SVM-RFE, we identified RSAD2 and IFI44L as key genes, and the Receiver Operating Characteristic (ROC) curve verification results showed high accuracy (Area Under the Curve, AUC > 0.7). ssGSEA showed that RSAD2 was involved in complement and coagulation cascade reactions, while IFI44L was related to myocardial contraction in the progression of heart failure. DSigDB prediction results showed that 6 drugs such as acetohexamide may have potential therapeutic effects on HF aggravated by respiratory diseases. Immune infiltration analysis revealed significant differences in eight immune cell types between HF patients and healthy controls. Our findings enhance the understanding of molecular interactions between respiratory diseases and heart failure, paving the way for future research and therapeutic strategies.

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme's active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Method: Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Results: Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC50) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC50 values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with KI = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. Conclusions: This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease.

Background: Oropouche virus (OROV), part of the Peribunyaviridae family, is an emerging pathogen causing Oropouche fever, a febrile illness endemic in South and Central America. Transmitted primarily through midge bites (Culicoides paraensis), OROV has no specific antiviral treatment or vaccine. This study aims to identify host-targeted therapeutics against OROV using computational approaches, offering a potential strategy for sustainable antiviral drug discovery. Methods: Virus-associated host targets were identified using the OMIM and GeneCards databases. The Enrichr and DSigDB platforms were used for drug prediction, filtering compounds based on Lipinski's rule for drug likeness. A protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape 3.10.3 software. Four key host targets-IL10, FASLG, PTPRC, and FCGR3A-were prioritized based on their roles in immune modulation and OROV pathogenesis. Molecular docking simulations were performed using the PyRx software to evaluate the binding affinities of selected small-molecule inhibitors-Acetohexamide, Deptropine, Methotrexate, Retinoic Acid, and 3-Azido-3-deoxythymidine-against the identified targets. Results: The PPI network analysis highlighted immune-mediated pathways such as Fc-gamma receptor signaling, cytokine control, and T-cell receptor signaling as critical intervention points. Molecular docking revealed strong binding affinities between the selected compounds and the prioritized targets, suggesting their potential efficacy as host-targeting antiviral candidates. Acetohexamide and Deptropine showed strong binding to multiple targets, indicating broad-spectrum antiviral potential. Further in vitro and in vivo validations are needed to confirm these findings and translate them into clinically relevant treatments. Conclusions: This study highlights the potential of using computational approaches to identify host-targeted therapeutics for Oropouche virus (OROV). By targeting key host proteins involved in immune modulation-IL10, FASLG, PTPRC, and FCGR3A-the selected compounds, Acetohexamide and Deptropine, demonstrate strong binding affinities, suggesting their potential as broad-spectrum antiviral candidates. Further experimental validation is needed to confirm their efficacy and potential for clinical application, offering a promising strategy for sustainable antiviral drug discovery.

Of all isoforms, human carbonic anhydrase II (PF00194; EC 4.2.1.1), which is mostly found in red cells, kidneys, and the eyes, plays a pivotal role in numerous physiological processes, and its dysregulation has been linked to the wide range of illnesses, such as glaucoma. Finding new inhibitors that target carbonic anhydrase II, therefore has great potential in drug discovery. Using drug repurposing approach, this study focused on the investigation of different drugs as Carbonic anhydrase II inhibitors and their structural studies using X-ray crystallography. For this purpose, 100 different drugs were evaluated for bovine and human carbonic anhydrase II inhibitory activity. Among all, two drugs, i.e. acetohexamide (1) and levosulpiride (54) were found to be active, with IC50 = 437.0 ± 0.2 and 1128 ± 0.75 μM, respectively. Mechanistic studies suggested that both drugs are competitive inhibitors of the human carbonic anhydrase II enzyme. The X-ray crystal structure analysis revealed that acetohexamide (1) interacts via terminal acetyl group with the active site residues of the carbonic anhydrase II enzyme, and showed strong hydrogen bonding with Zn, His94, His119, and Asn67. The sulfonamide group of levosulpiride was involved in strong hydrogen bonding with Zn, His94, His119, and Thr199. From in vivo studies, we found that carbonic anhydrase activity was significantly inhibited by the intraperitoneal administration of levosulpiride for up to 5 h. Our findings provide comprehensive insights for the optimization of the pharmacological profile of these drugs, and provide avenues for the exploration of different derivatives of these drugs with enhanced efficacy and fewer adverse effects.

Type 2 diabetes mellitus (T2DM) has become a serious public health problem both in our country and worldwide, being the most prevalent type of diabetes. The combined use of drugs in the treatment of T2DM leads to serious side effects, including gastrointestinal problems, liver toxicity, hypoglycemia, and treatment costs. Hence, there has been a growing emphasis on drugs that demonstrate dual interactions. Several studies have suggested that dual-target agents for peroxisome proliferator-activated receptor-γ (PPAR-γ) and alpha-glucosidase (α-glucosidase) could be a potent approach for treating patients with diabetes. We aim to develop new antidiabetic agents that target PPAR-γ and α-glucosidase enzymes using molecular modeling techniques. These compounds show dual interactions, are more effective, and have fewer side effects. The molecular docking method was employed to investigate the enzyme-ligand interaction mechanisms of 159 newly designed compounds with target enzymes. Additionally, we evaluated the ADME properties and pharmacokinetic suitability of these compounds based on Lipinski and Veber's rules. Compound 70, which exhibited favorable ADME properties, demonstrated more effective binding energy with both PPAR-γ and α-glucosidase enzymes (-12,16 kcal/mol, -10.07 kcal/mol) compared to the reference compounds of Acetohexamide (-9.31 kcal/mol, -7.48 kcal/mol) and Glibenclamide (-11.12 kcal/mol, -8.66 kcal/mol). Further, analyses of MM/PBSA binding free energy and molecular dynamics (MD) simulations were conducted for target enzymes with compound 70, which exhibited the most favorable binding affinities with both enzymes. Based on this information, our study aims to contribute to the development of new dual-target antidiabetic agents with improved efficacy, reduced side effects, and enhanced reliability for diabetes treatment.

Co-existence of life style disorders, like, Diabetes or Hypertension, increases risk of, treatment failure, deaths and developing drug-resistant TB. Concomitant administration of drugs to treat dual/multi-morbidities may alter their effectiveness, in additive/synergistic or adverse/antagonistic manner. We evaluated interactive effect of 7 anti-hyperglycaemic (HG) and 6 anti-hypertensive (HT) drugs on the inhibitory (MICs) and bactericidal (% killing of intracellular bacilli) activities of anti-TB drugs, Isoniazid (INH), Rifampicin (RFM), Ethambutol (EMB) and Streptomycin (STR) against M. tuberculosis. Five anti-HG drugs, namely, Acarbose, Acetohexamide, Glyburide, Repaglinide and Sitagliptin imparted either 'additive' or 'no effect' on the activities (inhibition or % killing) of all the four anti-TB drugs, as evident by their lower FICs (Fractional Inhibitory concentrations) and higher bacterial killing in combination. Metformin and Rosiglitazone, however, exerted adverse effect on the Ethambutol (FICs >2.0). All the six anti-HT drugs, namely, Atenolol, Hydrochlorothiazide, Ramipril, Valsartan, Nifedipine and Verapamil exerted either 'additive'/'synergistic' or 'no effect' on the activities of anti-TB drugs. These findings may help clinicians to select safe and helpful anti-HG or anti-HT drugs for TB patients, if, suffering with diabetes or hypertension like co-morbidities and receiving DOTs (a set regimen for the treatment of TB based on the WHO guidelines).

As the prevalence of diabetes rises, the use of antidiabetic drugs becomes more frequent. Thus, focusing on the effects of these drugs on water-sodium balance and electrolyte regulation is necessary. This review discusses the effects and the mechanisms behind them. Several sulfonylureas, such as chlorpropamide, methanesulfonamide, and tolbutamide, exhibit water-retaining properties. Other sulfonylureas, such as glipizide, glibenclamide, acetohexamide, and tolazamide, are not antidiuretic or even diuretic. Numerous clinical studies showed that metformin can reduce serum magnesium concentrations and may have an effect on the cardiovascular system, but the specific mechanism remains to be discussed. Different opinions exist about the mechanisms of thiazolidinedione-induced fluid retention. Sodium-glucose cotransporter 2 inhibitors can cause osmotic diuresis and natriuresis and elevated serum potassium and magnesium concentrations. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors can enhance urine sodium excretion. At the same time, increased urinary sodium caused by sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors reduce blood pressure and plasma volume, thereby protecting the heart. Insulin has a sodium-retaining effect and is also associated with hypokalemia, hypomagnesemia, and hypophosphatemia. Several of the aforementioned pathophysiological changes and mechanisms have been discussed, and conclusions have been drawn. However, further investigation and discussion are still warranted.

Aldo-keto reductase 1C3 (AKR1C3) plays a role in the detoxification and activation of clinical drugs by catalyzing reduction reactions. There are approximately 400 single-nucleotide polymorphisms (SNPs) in the AKR1C3 gene, but their impact on the enzyme activity is still unclear. This study aimed to clarify the effects of SNPs of AKR1C3 with more than 0.5% global minor allele frequency on the reductase activities for its typical substrates. Recombinant AKR1C3 wild-type and R66Q, E77G, C145Y, P180S, or R258C variants were constructed using insect Sf21 cells, and reductase activities for acetohexamide, doxorubicin, and loxoprofen by recombinant AKR1C3s were measured by liquid chromatography-tandem mass spectrometry. Among the variants tested, the C145Y variant showed remarkably low (6%-14% of wild type) intrinsic clearances of reductase activities for all three drugs. Reductase activities of these three drugs were measured using 34 individual Japanese liver cytosols, revealing that heterozygotes of the SNP g.55101G>A tended to show lower reductase activities for three drugs than homozygotes of the wild type. Furthermore, genotyping of the SNP g.55101G>A causing C145Y in 96 Caucasians, 166 African Americans, 192 Koreans, and 183 Japanese individuals was performed by polymerase chain reaction-restriction fragment length polymorphism. This allelic variant was specifically detected in Asians, with allele frequencies of 6.8% and 3.6% in Koreans and Japanese, respectively. To conclude, an AKR1C3 allele with the SNP g.55101G>A causing C145Y would be one of the causal factors for interindividual variabilities in the efficacy and toxicity of drugs reduced by AKR1C3. SIGNIFICANCE STATEMENT: This is the first study to clarify that the AKR1C3 allele with the SNP g.55101G>A causing C145Y results in a decrease in reductase activity. Since the allele was specifically observed in Asians, the allele would be a factor causing an interindividual variability in sensitivity of drug efficacy or toxicity of drugs reduced by AKR1C3 in Asians.

Enzymes of the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase superfamilies are involved in the reduction of compounds containing a ketone group. In most cases, multiple isoforms appear to be involved in the reduction of a compound, and the enzyme(s) that are responsible for the reaction in the human liver have not been elucidated. The purpose of this study was to quantitatively evaluate the contribution of each isoform to reduction reactions in the human liver. Recombinant cytosolic isoforms were constructed, i.e., AKR1C1, AKR1C2, AKR1C3, AKR1C4, and carbonyl reductase 1 (CBR1), and a microsomal isoform, 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), and their contributions to the reduction of 10 compounds were examined by extrapolating the relative expression of each reductase protein in human liver preparations to recombinant systems quantified by liquid chromatography-mass spectrometry. The reductase activities for acetohexamide, doxorubicin, haloperidol, loxoprofen, naloxone, oxcarbazepine, and pentoxifylline were predominantly catalyzed by cytosolic isoforms, and the sum of the contributions of individual cytosolic reductases was almost 100%. Interestingly, AKR1C3 showed the highest contribution to acetohexamide and loxoprofen reduction, although previous studies have revealed that CBR1 mainly metabolizes them. The reductase activities of bupropion, ketoprofen, and tolperisone were catalyzed by microsomal isoform(s), and the contributions of HSD11B1 were calculated to be 41%, 32%, and 104%, respectively. To our knowledge, this is the first study to quantitatively evaluate the contribution of each reductase to the reduction of drugs in the human liver. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to determine the contribution of aldo-keto reductase (AKR)-1C1, AKR1C2, AKR1C3, AKR1C4, carbonyl reductase 1, and 11β-hydroxysteroid dehydrogenase type 1 to drug reductions in the human liver by utilizing the relative expression factor approach. This study found that AKR1C3 contributes to the reduction of compounds at higher-than-expected rates.