Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones

Exploring the functional space of thiiranes as gelatinase inhibitors using click chemistry

“…When paired with many zinc-binding groups, the 4-alkynylmethoxyphenyl motif imparts selectivity towards ADAM protease inhibition, and against MMP inhibition. [32][33][34][35] Nonetheless, in the course of a comprehensive SAR study of the 4-alkynylmethoxyphenyl paired to thiol zinc-binding groups, Bandarage et al 25,36 observed several inhibitors having this pairing that showed both MMP-2 and ADAM-17 inhibitory activity. Our structure-activity data for MMP-2 inhibition are consistent with their data.…”

“…Potent inhibitors with dual MMP and TACE activity incorporating a butynyloxy tail with a different zinc-binding group (ZBG), were reported previously ( Figure 3). 25,26 Based on this observation, we synthesized the O-butynyloxy and O-pentynyloxy thiirane analogs for evaluation as gelatinase inhibitors. The synthetic route to these derivatives is depicted in Scheme 3.…”

Prediction of novel and selective TNF-alpha converting enzyme (TACE) inhibitors and characterization of correlative molecular descriptors by machine learning approaches

“…A total of 443 TACE inhibitors used in this work were collected from recently published papers [15,[18][19][20][21][23][24][25][26][27][29][30][31][32][33][34][35][36][37][38][39][40][41]. The majority of the tested inhibitors are efficient TACE inhibiting agents showing IC 50 value from 0.000066 mM to 100 mM.…”

“…With the combination of these two approaches, the explosion of novel non-hydroxamate TACE inhibitors was suddenly brought about [30][31][32][33][34]. In particular, based on molecular modeling study, researchers at Bristol-Myers Squibb Pharmaceutical Research Institute (BMSPRI) developed a highly plausible pharmacophore model to rationalize the observed TACE activity of hydroxamate and non-hydroxamate (hydantoins and barbiturate) TACE inhibitors [35], and then used this pharmacophore model to guide the design of some fresh heterocyclic non-hydroxamate TACE inhibitors such as triazolones, imidazolones and pyrimidine-2,4,6-trione inhibitors of TACE [32,33].…”

Regioselective synthesis and ab initio calculations of fused heterocycles thermally and under microwave irradiation

“…It was found that the final cyclocondensation reaction product depends mainly on the initial addition to the activated Introduction Sulfones 1-2 are a versatile class of compounds due to their applications in many pharmaceutical fields. [3][4][5][6][7][8][9] They have attracted the attention of many authors and great efforts have been made to develop new approaches to a variety of heterocycles incorporating phenylsulfonyl moiety for biological screening. Moreover, sulfone moiety is usually incorporated as an active part in many analgesic anti-inflammatory molecules available as drugs in the market such as celecoxib, 2,10 valdecoxib, 11 rofecoxib, 12 parecoxib, 13 etoricoxib, 14 tenoxicam, 15 piroxicam, 16 meloxicam, 17 lornoxicam, 18 ampiroxicam, 19 and nimesulide.…”