Synthesis and evaluation of 7-azaindole derivatives bearing benzocycloalkanone motifs as protein kinase inhibitors.

Protein kinases are important drug targets, especially in the area of oncology. This paper reports the synthesis and biological evaluation of new 7-azaindole derivatives bearing benzocycloalkanone motifs as potential protein kinase inhibitors. Four compounds 8g, 8h, 8i, and 8l were discovered to inhibit cyclin-dependent kinase 9 (CDK9/CyclinT) and/or Haspin kinase in the micromolar to nanomolar range. 8l was identified as the most potent Haspin inhibitor (IC50 = 14 nM), while 8g and 8h acted as dual inhibitors of CDK9/CyclinT and Haspin. These novel compounds constitute a promising starting point for the discovery of dual protein kinase inhibitors that have potential to be developed as anticancer agents, since both CDK9/CyclinT and Haspin are considered to be drug targets in oncology.

The monoamine oxidase inhibition properties of C6-mono- and N3/C6-disubstituted derivatives of 4(3H)-quinazolinone.

Parkinson's disease is characterised by the death of the nigrostriatal neurons and depletion of striatal dopamine. The standard symptomatic therapy consists of dopamine replacement with l-dopa, the metabolic precursor of dopamine, which represents the most effective treatment. Since monoamine oxidase (MAO) B is a key dopamine metabolising enzyme in the brain, MAO-B inhibitors are often used as adjuvants to l-dopa. In addition to the symptomatic benefits offered by MAO-B inhibitors, these drugs may also possess neuroprotective properties and possibly delay the progression of Parkinson's disease. Based on the therapeutic use of MAO-B inhibitors, the present study evaluates a series of mono- and disubstituted derivatives of 4(3H)-quinazolinone as potential inhibitors of recombinant human MAO-A and MAO-B. Twelve C6-monosubstituted and nine N3/C6-disubstituted 4(3H)-quinazolinone derivatives were synthesised, which led to the discovery of novel quinazolinone derivatives with micromolar and submicromolar activities as inhibitors of MAO-B. The most potent mono- and disubstituted derivatives exhibited IC50 values of 6.35 µM (7f) and 0.685 µM (8b), respectively. This study identifies suitable substitution patterns for the design of 4(3H)-quinazolinone derivatives as MAO-B inhibitors.

Synthesis and evaluation of 2-substituted 4(3H)-quinazolinone thioether derivatives as monoamine oxidase inhibitors.

In the present study, a series of fourteen 2-mercapto-4(3H)-quinazolinone derivatives was synthesised and evaluated as potential inhibitors of the human monoamine oxidase (MAO) enzymes. Quinazolinone is the oxidised form of quinazoline, and although this class has not yet been extensively explored as MAO inhibitors, it has been shown to possess a wide variety of biological activities. Among the quinazolinone derivatives investigated, seven compounds (IC50 < 1 µM) proved to be potent and specific MAO-B inhibitors, with the most potent inhibitor, 2-[(3-iodobenzyl)thio]quinazolin-4(3H)-one, exhibiting an IC50 value of 0.142 µM. Further investigation showed that this inhibitor is a reversible and competitive inhibitor of MAO-B with a Ki value of 0.068 µM. None of the test compounds were MAO-A inhibitors. Analysis of the structure-activity relationships (SARs) for MAO-B inhibition shows that substitution on the C2 position of quinazolinone with a benzylthio moiety bearing a Cl, Br or I on the meta position yields the most potent inhibitors of the series. In contrast, substitution with the unsubstituted benzylthio moiety (IC50 = 3.03 µM) resulted in significantly weaker inhibition activity towards MAO-B. This study suggests that quinazolinones are promising leads for the development of selective MAO-B inhibitors which may be used for the treatment of neurodegenerative disorders such as Parkinson's disease.

Exploration of 7-azaindole-coumaranone hybrids and their analogues as protein kinase inhibitors.

7-Azaindole has been labelled a privileged scaffold for the design of new potent inhibitors of protein kinases. In this paper, we determined the inhibition profiles of novel mono- and disubstituted derivatives of 7-azaindole-coumaranone hybrids on various disease-related protein kinases. Eight hit compounds were identified, including a potent Haspin inhibitor with an IC50 value of 0.15 µM. An interesting observation was that all active monosubstituted compounds displayed dual inhibition for Haspin and GSK-3ß, while disubstituted derivatives inhibited GSK-3ß and LmCK1 from Leishmania major parasite. Analyses of structure activity relationships (SARs) also revealed that mono-substitution with para-fluorobenzyloxy ring produced an equipotent inhibition of Haspin and GSK-3ß. Haspin and GSK-3ß are relevant targets for developing new anticancer agents while LmCK1 is an innovative target for leishmanicidal drugs. Novel compounds reported in this paper constitute promising starting points for the development of new anticancer and leishmanicidal drugs.

Synthesis and evaluation of C3 substituted chalcone-based derivatives of 7-azaindole as protein kinase inhibitors.

Chalcones are a group of naturally occurring or synthetic compounds which possess a wide range of biological activities. In this paper, a series of twenty-three 7-azaindole-chalcone hybrids (5a-w) were synthesized and evaluated as potential protein kinase inhibitors. Analyses of structure-activity relationships revealed that some of these compounds exhibit significant activity against Haspin kinase, with compounds 5f and 5q exhibiting IC50 values of 0.47 and 0.41 µM, respectively. Furthermore, 5f also inhibits cyclin-dependent kinase 9 (CDK9/CyclinT) in a micromolar potency (IC50  = 2.26 µM). This novel dual-target inhibitor is a promising lead for the development of chemopreventive/chemotherapeutic agents.