Recyclization of 2,3-Disubstituted 5-Arylamino-2,5-dihydro-1,2,4-thiadiazoles and Related Salts into Benzothiazole Derivatives

Renskii, M. A.; Zyabrev, V. S.

doi:10.1023/b:rugc.0000007669.57383.e6

Cited by 1 publication

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“…While the core 1,2,4-thiadiazole heterocycle 3 may appear benign, many such compounds can react quite readily with thiols − but not other functional groups like alcohols or amines. , Many properties of 1,2,4-thiadiazoles have been documented. − The 1,2,4-thiadiazole core can be susceptible to ring-opening reactions, recyclization side products, and nonenzymatic reductions. − Notably, this scaffold is similar to the “het_thio_N_5A” PAINS substructure, although it differs by resonance and substitution at the N2-position, meaning this chemotype could bypass some PAINS filters depending on its structural representation and certain chemoinformatic parameters …”

Section: Resultsmentioning

confidence: 99%

PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS

et al. 2015

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Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compounds, while understanding the chemical basis for these adverse behaviors often goes unexplored in pursuit of lead compounds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compounds. Herein, we characterize the chemical basis for assay interference and promiscuous enzymatic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compounds (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compounds react covalently with cysteines on multiple proteins. Unfortunately, compounds containing these chemotypes have been published as screening actives in reputable journals and even touted as chemical probes or preclinical candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compounds, guide screening library design, and prevent follow-up on undesirable chemical matter.

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