Synthesis of Desaza Analogues of Annomontine and Canthin‐4‐one Alkaloids

Abstract

1-Acetylcarbazoles are readily converted to 3-desazacanthin-4-ones upon treatment with Bredereck's reagent, but in contrast to canthin-4-ones, these do not undergo ring transformation reactions with guanidine. Only after N-protection (methyl or 2-(trimethylsilyl)ethoxymethyl group), 2-desaza analogues of the alkaloid annomontine are accessible via the enaminoketones obtained by condensation with Bredereck's reagent. One of the annomontine analogues is an inhibitor of the Plasmodium falciparum CDC-like kinases (CLK) and shows antimalarial activity.

Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2

“…The screening hit GeA-69 ( 1 ) was part of a focused library from the Bracher lab, originally designed for the improvement of kinase inhibitors derived from the 1-(aminopyrimidyl)-β-carboline alkaloid annomontine. 13 The SAR studies on screening hit GeA-69 ( 1 ) are described in the following compound library generated as potential PARP14 MD2 inhibitors ( Fig. 3 ).…”

“…3 ). In this library, the β-carboline ring system was replaced by its deaza analogue carbazole, and a number of aromatic and heteroaromatic rings were attached to position 1 ( Scheme 1 ) using Suzuki-Miyaura cross coupling reactions of known 1-bromocarbazole 14 with commercially available or synthesised boronic acids and esters to give compounds 3 – 12 ( Scheme 1 ).

Figure 3 SAR studies of carbazoles GeA-69 ( 1 ) and 2 .

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Canthin‐4‐ones as Novel Antibacterial Agents

“…3‐Desazacanthin‐4‐one ( 12 ) was available from previous work . Since the 5‐(3‐pyridyl)‐canthin‐4‐one ( 24h ) turned out to be one of the most interesting antimicrobials in this investigation (see below), we also prepared the corresponding 3‐desaza analog 28 .…”

“…This prompted us to perform a deeper investigation of the antimicrobial potential of natural and synthetic canthin‐4‐ones. In addition to the alkaloids 1 – 3 , canthin‐4‐one ( 6 ), synthetic analogs 6‐phenylcanthin‐4‐one ( 7 ), 5‐iodo‐6‐methylcanthin‐4‐one ( 8 ), and 6‐methyl‐5‐phenylcanthin‐4‐one ( 9 ), as well as reduced analogs 10 and 11 and the 3‐desaza analog 12 were available from previous work . In combination with new compounds described in this article, this collection of compounds enabled us to investigate the impact of partial structures of the canthin‐4‐one backbone and of substituents on the ring system on their antimicrobial activities.…”

One‐Pot Three‐Component Synthesis of Pyrido[2,3‐c]carbazole Derivatives in EtOH under Catalyst‐Free Conditions

“…Carbazole is a very useful medical molecule with significant biological and pharmacological activities, which include antiviral , anticancer , and antifungal activities in its derivatives. They are also used as various kinds of inhibitors, such as angiotensin converting enzyme inhibitors , lipoxygenase inhibitors , the Plasmodium falciparum CDC‐like kinases , and mycobacterium tuberculosis inhibitors . Some of them have been developed as clinical drugs (Fig.…”