Abstract:The indole ring system is a prominent partial structure of several protein kinase inhibitor families. The title compound is the first example of a 5-substituted indolyl squaryl chloride with free indole nitrogen. It has been synthesized by reaction of 5-methoxyindole with squaric acid dichloride in diethyl ether and its IR, 1 H-NMR, 13 C-NMR, MS, UV and HPLC data are presented. This compound may prove to be a rather useful building block for the preparation of various derivatives for biological studies. Keywords: Friedel-Crafts acylation; indole; squaric acid dichlorideThe indole ring system is a prominent partial structure of several protein kinase inhibitor families, e.g., bisindolylmaleimides (BIMs) [1], staurosporine analogues [2], and paullones [3,4]. With the aim to develop protein kinase inhibitors based on novel scaffolds by structure-guided design methods [5] we were interested to combine the indole ring system with squaric acid derived structure elements. The latter have recently been highlighted as "unusual" chemical structures with high potential for drug development [6]. A review of the literature revealed that only few squarylated indoles are described [7][8][9]. Only a single study mentioned a 3-chloro-4-(1H-indol-3-yl)cyclobut-3-ene-1,2-dione unsubstituted at the indole nitrogen [10]. We here report the detailed synthesis procedure of the title compound 3 as first example of a 5-substituted indolylchlorocyclobutenedione with free indole nitrogen. This compound may prove to be a rather useful building block for the preparation of various derivatives for biological studies.According to the high reactivity of the indole ring system for electrophilic attack in 3-position, the synthesis was carried out by means of a Friedel-Crafts acylation reaction from 5-methoxyindole (2) OPEN ACCESS

Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

2,3,4-Trioxo-1-(1H-pyrrolo[2,3-b]pyridin-7-ium-7-yl)-cyclobutan-1-ide was obtained by reaction of squaric acid with 7-azaindole in acetic anhydride.