7-Bromo-1-methyl-2-phenyl-1H-indole-3-carbonitrile

The title compound was prepared by electrophilic aromatic substitution of 7-bromo-1-methyl-2-phenyl-1H-indole with NCTS (N-cyano-N-phenyl-p-toluenesulfonamide). The structural identity of the title compound was proven by elemental analysis and spectroscopic methods (IR, NMR, APCI-MS). Purity was assessed by two independent HPLC methods

Structural simplification of paullones: Indole derivatives as antitrypanosomal agents

Trypanosoma- und Leishmania-Parasiten lösen verheerende Infektionskrankheiten in den Tropen aus, die von der Weltgesundheitsorganisation zu den vernachlässigten Tropenkrankheiten gezählt werden. Die aktuell zugelassenen Chemotherapeutika erfüllen die an Arzneimittel zur Behandlung dieser Krankheiten gestellten Anforderungen zu einem großen Teil nicht. Obwohl die Forschungsaktivitäten in den letzten Jahren deutlich zugenommen haben, ist die Entwicklung neuer Wirkstoffe gegen die Parasiten dringend nötig. Paullon-N5-acetamide waren eine vielversprechende Wirkstoffgruppe gegen die einzelligen Erreger. Entsprechend substituierte Paullone hemmen die Proliferation der Protozoen durch eine Inhibition der Trypanothionsynthetase (TryS), eines essenziellen, an der parasitären Redoxhomöostase beteiligten und parasitenspezifischen Enzyms, das nicht in den Wirtsorganismen vorkommt. Paullone eignen sich jedoch nicht als mögliche neue Wirkstoffe, weil sie keine angemessenen Eigenschaften im Sinne der druglikeness besitzen und beispielsweise nur schlecht in wässrigen Medien löslich sind. Die wässrige Löslichkeit ist eine wichtige Eigenschaft von Arzneistoffen zur Behandlung von Tropenkrankheiten, denn die Arzneistoffe sollten aufgrund der infrastrukturellen Verhältnisse der betroffenen Länder oral appliziert werden können. Das Ziel dieser Dissertation war es, durch molekulare Operationen die Paullone so zu vereinfachen, dass Verbindungen entstehen, die die TryS inhibieren, das Parasitenwachstum unterdrücken und gleichzeitig eine verbesserte druglikeness und Löslichkeit besitzen. Im Rahmen der Arbeit wurden verschiedene Struktur-Aktivitäts- und Struktur-Eigenschafts-Beziehungen rund um ein Strukturelement der Paullone, einen Indolylacetamid-Grundkörper, aufgestellt. So wurden Substituenten identifiziert mit denen die antiparasitäre Wirkung gegenüber Trypanosoma brucei brucei-Blutstromform-Parasiten und/oder die druglikeness-Eigenschaften modifiziert werden können. Viele der identifizierten antiparasitären Verbindungen besitzen jedoch eine hohe Lipophilie, die vermutlich zu deren mangelhafter wässriger Löslichkeit beiträgt. Dennoch wurden auch Verbindungen gefunden, die angemessene Löslichkeitseigenschaften besitzen. Nach vorläufigen Ergebnissen hemmt jedoch keine der untersuchten Verbindungen die ursprünglich als Zielenzym adressierte Trypanothionsynthetase von Leishmania infantum. Es sind also andere Zielstrukturen für die antitrypanosomale Wirkung verantwortlich. Die Ergebnisse der vorgelegten Arbeit können als Basis für die Entwicklung neuer Chemotherapeutika zur Behandlung parasitärer vernachlässigter Tropenerkrankungen dienen.Trypanosoma and Leishmania parasites cause devastating infectious diseases in the tropics, which are categorized by the World Health Organization as neglected tropical diseases. To a large extent, the currently approved chemotherapeutic agents do not meet the requirements placed on drugs for the treatment of these diseases. Although research activities have increased significantly in recent years, the development of new agents against the parasites is urgently needed. Paullone-N5-acetamides have been a promising group of agents against the unicellular pathogens. Appropriately substituted paullones inhibit protozoan proliferation by inhibiting trypanothione synthetase (TryS), an essential enzyme involved in parasitic redox homeostasis that is specific to parasites and does not occur in mammalian hosts. However, paullones are not suitable as potential new drugs because they lack appropriate properties in terms of druglikeness and, for example, are poorly soluble in aqueous media. Aqueous solubility is an important property of drugs for the treatment of tropical diseases, because the drugs should be able to be applied orally due to the infrastructural conditions of the affected countries. The aim of this dissertation was the structural simplification of paullones through molecular operations to find compounds that inhibit TryS, suppress parasite growth, and at the same time have improved druglikeness and solubility. As part of the work, various structure–activity and structure–property relationships were established around a structural element of paullones, an indolylacetamide backbone. Thus, substituents modifying antiparasitic activity against Trypanosoma brucei brucei bloodstream form parasites and/or druglikeness properties were identified. However, many of the identified antiparasitic compounds possess high lipophilicity, which probably contributes to their poor aqueous solubility. Nevertheless, compounds possessing adequate solubility properties were also found. However, according to preliminary results, none of the investigated compounds inhibits the trypanothione synthetase of Leishmania infantum, which was originally addressed as a target enzyme. Thus, other targets are responsible for the antitrypanosomal effect. The results of the presented work may serve as a basis for the development of new chemotherapeutic agents for the treatment of parasitic neglected tropical diseases

7-Bromo-1-methyl-2-phenyl-1H-indole-3-carbonitrile

The title compound was prepared by electrophilic aromatic substitution of 7-bromo-1-methyl-2-phenyl-1H-indole with NCTS (N-cyano-N-phenyl-p-toluenesulfonamide). The structural identity of the title compound was proven by elemental analysis and spectroscopic methods (IR, NMR, APCI-MS). Purity was assessed by two independent HPLC methods

7-Bromo-1-methyl-2-phenyl-1H-indole-3-carbonitrile

The title compound was prepared by electrophilic aromatic substitution of 7-bromo-1-methyl-2-phenyl-1H-indole with NCTS (N-cyano-N-phenyl-p-toluenesulfonamide). The structural identity of the title compound was proven by elemental analysis and spectroscopic methods (IR, NMR, APCI-MS). Purity was assessed by two independent HPLC methods

The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones.

Severe infections with potentially fatal outcomes are caused by parasites from the genera Trypanosoma and Leishmania (class Kinetoplastea). The diseases affect people of remote areas in the tropics and subtropics with limited access to adequate health care. Besides insufficient diagnostics, treatment options are limited, with tenuous developments in recent years. Therefore, new antitrypanosomal antiinfectives are required to fight these maladies. In the presented approach, new compounds were developed and tested on the target trypanothione synthetase (TryS). This enzyme is crucial to the kinetoplastids' unique trypanothione-based thiol redox metabolism and thus for pathogen survival. Preceding studies have shown that N5-substituted paullones display antitrypanosomal activity as well as TryS inhibition. Herein, this compound class was further examined regarding the structure-activity relationships (SAR). Diverse benzazepinone derivatives were designed and tested in cell-based assays on bloodstream Trypanosoma brucei brucei (T. b. brucei) and intracellular amastigotes of Leishmania infantum (L. infantum) as well as in enzyme-based assays on L. infantum TryS (LiTryS) and T. b. brucei TryS (TbTryS). While an exchange of just the substituent in the 9-position of paullones led to potent inhibitors on LiTryS and T. b. brucei parasites, new compounds lacking the indole moiety showed a total loss of activity in both assays. Conclusively, the indole as part of the paullone structure is pivotal for keeping the TryS inhibitory and antitrypanosomal activity of this substance class