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

Abstract

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-3β, while disubstituted derivatives inhibited GSK-3β 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-3β. Haspin and GSK-3β 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.

Keywords: 7-Azaindole; Anticancer drugs; Coumaranone; GSK-3β; Haspin; Leishmanicidal drugs; LmCK1; Polypharmacology; Protein kinase.