Synthesis and Selective Functionalization of Thiadiazine 1,1-Dioxides with Efficacy in a Model of Huntington’s Disease

Abstract

The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington’s disease.

The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington’s Disease

“…205 Further, several dihydropyrimidinones were designed as HSP70 chaperone agonists based on structural similarities with MALI-271 (152). 206 Among them, the hydroxamic acid derivative of MAL1−271 (152), namely, compound 153, exhibited promising HSP70 chaperone agonist activity. Compound 153 effectively suppressed the formation of toxic aggregates in HEK293H cells expressing Httex1-17Q without inhibiting HDAC.…”

“…Dihydropyrimidinone (MALI-271, 152 ) is a known agonist of HSP70 that reduces α-synuclein aggregation in neurodegenerative disease models (yeast expressing mHttex1-104Q) . Further, several dihydropyrimidinones were designed as HSP70 chaperone agonists based on structural similarities with MALI-271 ( 152 ) . Among them, the hydroxamic acid derivative of MAL1–271 ( 152 ), namely, compound 153 , exhibited promising HSP70 chaperone agonist activity.…”

Sulfamide instead of urea in Biginelli reaction: from black box to reality

“…The first one is a particular case of solving the task of isosteric replacement in Biginelli-type compound MAL1-127, active in a model of Huntington's disease. 12 Another paper obtained a bicyclic structure with a specific methylene-active component: hexane-1,3-dione (Fig. 1C).…”

2,3-Dihydro-1,2,6-thiadiazine 1-Oxides by Biginelli-Type Reactions with Sulfonimidamides under Mechanochemical Conditions

“…If successful, E would represent heteroatomcontaining chiral analogues of dihydropyrimidinones, which are known to display a wide variety of biological activities. 16,17 An initial experiment with p-tolyl sulfonimidamide (1a), 4chlorobenzaldehyde (2a), and β-keto ester 3a as representative substrates using a mortar and pestle for the grinding process provided 2,3-dihydro-1,2,6-thiadiazine 1-oxide 4a in 33% yield after 5 min. Being delighted by this very promising result, the subsequent studies were performed in an automated planetary ball mill (PM, Fritsch Pulverisette 7; for details, see footnote a of Table 1 and the Supporting Information).…”

“…Being aware of the aforementioned benefits of mechanochemical protocols, we wondered if partially saturated cyclic sulfonimidamides E could be prepared by MCR-type Biginelli reactions using simple starting materials under mechanochemical conditions. If successful, E would represent heteroatom-containing chiral analogues of dihydropyrimidinones, which are known to display a wide variety of biological activities. , …”