3-Hydroxy-1H-quinazoline-2,4-dione as a New Scaffold To Develop Potent and Selective Inhibitors of the Tumor-Associated Carbonic Anhydrases IX and XII

Abstract

In this paper, we describe the discovery of the 3-hydroxyquinazoline-2,4-dione as a useful scaffold to obtain potent inhibitors of the tumor-associated human carbonic anhydrases (hCAs) IX and XII. A set of derivatives (1-29), bearing different substituents on the fused benzo ring (Cl, NO, NH, CF, ureido, amido, heterocycles), were synthesized, and several of them showed nanomolar activity in inhibiting the hCA IX and XII isoforms, while they were ineffective against the cytosolic enzymes hCAs I and II. Some selected compounds were tested for their antiproliferative activity against HT-29 colon cancer cell lines. After 48 h of treatment with the lower dose (30 μM), derivatives 12, 14, 15, and 19 were significantly active, inducing a mortality by about 50% in both normoxia and hypoxia. This finding led us to hypothesize for these compounds more than one mechanism of action involving both CAs IX and XII and other not yet identified target(s).

Synthesis and characterization of the first inhibitor ofN-acylphosphatidylethanolamine phospholipase D (NAPE-PLD)

“…Next, we turned our attention to the quinazolinedione nucleus, which closely resembles scaffolds contributing to the activity of several metallo-enzyme inhibitors. 21 Methylation of its endocyclic nitrogens yielded the single-methylated derivatives, 7 and 8 , as well as the double-methylated derivative 9 . Each of these compounds retained some inhibitory activity, although weaker than the parent molecule (Chart 1).…”

Characterisation of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification

“…This complex has been reported to possess 3′-5′ exonuclease activity and, based on its ability to excise terminally mismatched ribonucleotides, one function ascribed to nsp14-nsp10 (by analogy with replicative DNA polymerases) is ′proofreading′ activity 3,10 , although other key roles in viral replication have been postulated 11 . Consistent with a role in proofreading of maintaining genome stability, nuclease-inactivating mutations in CoV DEDD motifs cause an elevated level of replication errors, impaired replication and in some cases lethal mutagenesis 4,5,12 . Moreover, nsp14 interacts with the CoV RNA-dependent RNA polymerase (RdRp), (i.e.…”

“…Perhaps necessarily, CoVs typically have a replication fidelity rate of an order of 10 -6 to 10 -7 , which is several orders of magnitude more accurate than that of most RNA viruses (typically ~10 -3 to 10 -5 ) 2 . In order to maintain the fidelity of these genomes during replication, CoVs rely upon a complex of two non-structural proteins, nsp14 (also known as ExoN) and nsp10 [2][3][4] . The importance of this enhanced level of replication fidelity has been demonstrated in studies that disrupt or inactivate the activity of nsp14-nsp10, where reduced virulence and pathogenesis is seen in mouse and cellular models [4][5][6] .…”

“…In order to maintain the fidelity of these genomes during replication, CoVs rely upon a complex of two non-structural proteins, nsp14 (also known as ExoN) and nsp10 [2][3][4] . The importance of this enhanced level of replication fidelity has been demonstrated in studies that disrupt or inactivate the activity of nsp14-nsp10, where reduced virulence and pathogenesis is seen in mouse and cellular models [4][5][6] . Therefore, targeting nsp14-nsp10 is an attractive therapeutic strategy, either as a standalone option or as an adjuvant to other agents that target other features of the replication cycle of the virus 7 .…”

Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

“…These compounds were unable to inhibit cytosolic isoforms hCA I as well as hCA II and displayed K i s > 10 000 for both isoforms. 305 N'-phenyl-N-hydroxyureas were found to be selective inhibitors for tumor-associated isoforms hCA IX and hCA II.…”