Thiazide and other Cl-benzenesulfonamide-bearing clinical drug affinities for human carbonic anhydrases

Abstract

Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human body. Despite their vital functions, they are also responsible for, or implicated in, numerous ailments and diseases such as glaucoma, high altitude sickness, and cancer. Because CA isoforms are highly homologous, clinical drugs designed to inhibit enzymatic activity of a particular isoform, can also bind to others with similar affinity causing toxic side effects. In this study, the affinities of twelve CA isoforms have been determined for nineteen clinically used drugs used to treat hypertension related diseases, i.e. thiazides, indapamide, and metolazone. Their affinities were determined using a fluorescent thermal shift assay. Stopped flow assay and isothermal titration calorimetry were also employed on a subset of compounds and proteins to confirm inhibition of CA enzymatic activity and verify the quantitative agreement between different assays. The findings of this study showed that pharmaceuticals could bind to human CA isoforms with variable affinities and inhibit their catalytic activity, even though the drug was intended to interact with a different (non-CA) protein target. Relatively minor structural changes of the compounds may cause significant changes in affinity and selectivity for a particular CA isoform.

Candidates for Repurposing as Anti-Virulence Agents Based on the Structural Profile Analysis of Microbial Collagenase Inhibitors

“…These results are similar with the pharmacological profile of benzthiazide. Contrary to other thiazide class compounds, it binds strongly to all human carbonic anhydrases isoforms coordinating the zinc ion through the sulfonamide group [65].…”

Photodegradation and In Silico Molecular Docking Study of a Diuretic Drug: Clopamide

“…Clopamide (CPD, 1 ), a trisubstituted benzene derivative with a sulfonamide chromophore as one of the substituents, is an oral diuretic , with the same aromatic sulfonamide basis as thiazide diuretics. , It possesses features comparable to those of thiazide class diuretics, which block sodium reabsorption in the proximal renal tubule while boosting release of chloride ions, consequently with increased waste excretion. , Clopamide ( 1 ) is increasingly being used to treat hypertension and excessive fluid retention in serious illnesses such as cardiac failure, nephrosis, chronic kidney failure, and cirrhosis . Previous research has shown that a once-daily fixed medication combination of 5 mg of clopamide, 10 mg of endralazine, and 10 mg of pindolol can be effective in the management of blood pressure in roughly 90% of individuals with mild to severe hypertension .…”