PURPOSE OF REVIEWTo review the management of Idiopathic Intracranial Hypertension (IIH) with co-existing conditions affecting therapy: obesity, sulfa allergy, nephrolithiasis, and pregnancy.RECENT FINDINGSThe IIH-WT trial showed that bariatric surgery is currently the most effective method for obese patients with IIH to lose weight, leading to normalization of CSF pressure in many cases. Allergy to sulfonamide antibiotics does not preclude the use of acetazolamide; rather, penicillin allergy or multiple drug allergies are the strongest predictor of a hypersensitivity reaction. Carbonic anhydrase inhibitors should be avoided in individuals with a personal history of nephrolithiasis; the risk of renal stones increases with concomitant use of other medications with the potential for nephrolithiasis. Glucagon-like peptide-1 receptor antagonists (GLP-1RA) are promising non-surgical weight loss options although preliminary studies have not demonstrated considerable impact on papilledema, headache or vision. Women with IIH have high rates of pregnancy complications partly related to obesity. Recommendations for weight gain or loss during gestation are controversial. Recent studies show better outcomes in obese women who maintain or lose weight while pregnant including gestational diabetes, pre-eclampsia and emergency caesarian section. Progress continues in the search for the cause and best treatments for IIH. Larger multicenter trials of GLP-1RA are needed to determine their efficacy.

01 Apr 2025·Molecular Diversity

Synthesis, molecular docking and molecular dynamics simulations, drug-likeness studies, ADMET prediction and biological evaluation of novel pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors

Article

Author: Tunca, Ekrem ; Kasımoğulları, Rahmi ; Yetek, İrfan ; Mert, Samet ; Bayrakdar, Alpaslan

AbstractPyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using FT-IR, 1H-NMR, 13C-NMR and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.063–3.368 µM for hCA I and 0.007–4.235 µM for hCA II. Molecular docking studies were performed between the most active compounds 6a, 6b and the reference inhibitor, acetazolamide (AAZ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ. ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50 ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations.Graphical abstractSynthesis, molecular docking, molecular dynamics simulations, drug-likeness, ADMET prediction and biological evaluation of pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors

01 Apr 2025·International Journal of Biological Macromolecules

Development of pyrazolo[1,5-a]pyrimidine-grafted coumarins as selective carbonic anhydrase inhibitors and tubulin polymerization inhibitors with potent anticancer activity

Article

Author: Nocentini, Alessio ; Eldehna, Wagdy M ; Abdel-Aziz, Hatem A ; Abdelrahman, Mohamed A ; Elkotamy, Mahmoud S ; Alkabbani, Mahmoud Abdelrahman ; Giovannuzzi, Simone ; Supuran, Claudiu T ; Abou-Seri, Sahar M

This study presents the design, synthesis, and evaluation of a novel series of coumarin-based compounds (9a-t) as potential anticancer agents. The compounds were strategically designed to inhibit cancer-related carbonic anhydrase (CA) isoforms IX and XII and tubulin polymerization. Two approaches were employed for CA inhibition: utilizing the coumarin motif to occlude the CA active site entrance and incorporating zinc-binding groups (sulfonamide, carboxylic acid, and thiol) to interact with the catalytic zinc ion. The target compounds were also designed to inhibit tubulin polymerization by combining the privileged coumarin and pyrazolo[1,5-a]pyrimidine scaffolds. Biological evaluation of the target compounds (9a-t) revealed that sulfonamide-containing derivatives 9 h and 9r exhibited potent inhibitory activity in the low nanomolar range against CA IX (K_i = 23 and 14 nM, respectively) and CA XII (K_i = 6 and 17 nM, respectively). In NCI-60 human tumor cell line screening, compounds 9 k, 9 m, and 9q demonstrated broad-spectrum anti-proliferative activity in the five-dose assay with MG-MID values of 7.31 μM, 10.68 μM, and 5.92 μM, respectively. Compound 9 m showed significant tubulin polymerization inhibition with an IC₅₀ = 5.28 μM, surpassing the efficacy of colchicine. Cell cycle analysis in MDA-MB-231 breast cancer cells revealed G2/M phase arrest for 9 m, which induced significant apoptosis and modulated apoptotic markers. Molecular docking studies provided insights into the binding modes of the compounds with CA IX, CA XII, and tubulin. ADMET and toxicity predictions were performed to assess the drug-like properties of the compounds. These findings pave the way for further optimization of the coumarin scaffold to develop dual inhibitors of carbonic anhydrase IX/XII and tubulin polymerization.

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma	Preclinical	Australia	Commonwealth Scientific & Industrial Research Organisation	-

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