Chlorothiazide. How the thiazides evolved as antihypertensive therapy.

Abstract

-have left little time to look back for looking forward, unless invited to do so. This is about chlorothiazide, how the thiazides evolved, and how they were expected to relate to edema and hypertension. Saluretics: Concepts and MethodologyMy Wisconsin training helped create a capability to identify clinical correlates of a "disease" with a best relevant expression of that function for manipulation in a most appropriate laboratory animal. Discovery of the thiazides was a second example of this from our research. The first example was the competitive inhibition of penicillin renal tubular secretion by first p-aminohippurate then ultimately probenecid (Benemid). 12By the time the probenecid work was completed, our renal clearance capability was well developed. We had started getting control of the fast-moving changes in electrolyte blood and urine chemistry, which we had to do precisely in order to use the clearance technique and concepts of how the kidney related to salt and water balance to assess diuretics. That took a while. Clinical CorrelatesSo far as I was concerned in the 1940s, the concentrations of Na + , K + , Cl~, and HCO 3 " in extracellularextravascular fluid, plasma water, and glomerular ultrafiltrate were conveniently close to being the same. Consequently, an alteration (inhibition) of reabsorption of equivalent Na + and Cl" ions as the glomerular ultrafiltrate passed along the lumen of the tubule would

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

“…These drugs, mainly used as diuretics, contain the benzothiadiazine group in their structure. This diuretic class with the first-in-class drug chlorothiazide was introduced in 1957 upon chemical modification of CA inhibitors [ 32 , 33 ]. Currently, thiazide diuretics are often used as first-line treatment for hypertension, despite that their exact mechanism of action is still unclear–it depends on the time course of the drug use: the acute action relies on the inhibition of Na + /Cl - cotransporter, while the mechanism of chronic action still has to be clarified [ 34 ].…”

Crystal structure from X-ray powder diffraction data, DFT-D calculation, Hirshfeld surface analysis, and energy frameworks of (RS)-trichlormethiazide

“…Trichlormethiazide (TCMZ), systematic name 6-chloro-3-(dichloromethyl)-1,1-dioxo-3,4-dihydro-2H-1 6 ,2,4-benzothiadiazine-7-sulfonamide (C 8 H 8 Cl 3 N 3 O 4 S 2 ), is a diuretic drug derived from thiazide, the precursor of a classic family of diuretic compounds, discovered in the 1950s. The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril in 1958 (Beyer, 1993). The compound under study, trichlormethiazide, has a similar chemical structure to hydrochlorothiazide, the most prescribed member of the group (Hripcsak et al, 2020).…”

Stability and Degradation Pathways of N-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

“…Hydrochlorothiazide (1, 6-chloro-3,4-dihydro-2H-benzo[e]- [1,2,4]thiadiazine-7-sulfonamide 1,1-dioxide, HCT, Scheme 1) was developed and put on the market in the late 1950s as one of the first efficient antihypertensive drugs. 1−6 Despite the fact that it has been on the market for more than 60 years, it still constitutes a backbone of antihypertensive therapy as a key component of many fixed dose combination products with angiotensin receptor blockers, ACE inhibitors, and other antihypertensive agents.…”

“…Indeed, literature reports already highlight the preparation of Nnitroso-hydrochlorothiazide (2, 6-chloro-4-nitroso-3,4-dihydro-2H-benzo[e] [1,2,4]thiadiazine-7-sulfonamide 1,1-dioxide, NO-HCT, Scheme 1); 37,38 however, its reactivity was not explored in a broader context. In this report, we demonstrate that NO-HCT 2 is unstable in aqueous conditions at pH 1 to 8 and readily decomposes to several degradation products among which formaldehyde, aminobenzenesulfonic acid (3, 2-amino-4chloro-5-sulfamoylbenzenesulfonic acid, ABSA, Scheme 1), thiatriazine (4, 6-chloro-2H-benzo[e] [1,2,3,4]thiatriazine-7sulfonamide 1,1-dioxide, Scheme 1), and HCT 1 are the predominant ones. Moreover, independent synthesis of the HCT-diazonium salt (5, 5-chloro-2,4-disulfamoylbenzenediazonium, Scheme 1) and study of its stability and reactivity have demonstrated that it is relatively stable only in highly acidic and anhydrous conditions in aprotic solvents (e.g., acetonitrile), whereas it decomposes rapidly in neutral or acidic aqueous medium to ABSA 3 instead of the typical diazonium salt hydrolysis and reduction products, which were not detected in the NO-HCT 2 degradation pathway.…”