Preliminary Communication For reprint orders, please contact: reprints@future-science.com Novel effective antibacterial small-molecules against Staphylococcus and Enterococcus strains Kaveh Yasrebi 1 , Nico Schade 1 , Emmanuel Tola Adeniyi 2 , Bj¨ orn Wecklein 2 , Alba Ymeraj 2 , Tobias Hertlein 2 , Knut Ohlsen 2 , Sibel Suzen 3 , Michael Lalk 4 , Dieter Str ¨ ohl 5 & Andreas Hilgeroth* ,1 1 Institute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany 2 Institute of Molecular Infection Biology, Julius Maximilians University Wuerzburg, 97080 Wuerzburg, Germany 3 Faculty of Pharmacy, Ankara University, 06100 Ankara, Turkey 4 Institute of Biochemistry, Ernst Moritz Arndt University Greifswald, 17487 Greifswald, Germany 5 Institute of Chemistry, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany *Author for correspondence: andreas.hilgeroth@pharmazie.uni-halle.de Background: Resistance developments against established antibiotics are an emerging problem for an- tibacterial therapies. Novel antibiotics are urgently needed. Materials & methods: We developed novel small-molecule antibacterials which are easily accessible in a simple one-pot synthesis. The central cy- clopentaindole core is substituted with two indole residues. Various indole and cyclopentane substituents have been introduced. Additionally, frst indole substituted propene compounds as ring-open variants of the cyclopentaindoles have been yielded and evaluated as antibacterials against Staphylococcus aureus and Enterococcus strains. Results: Most effective compounds have been those with a bromo cyclopentane and a chloro indole substitution. First lead compounds were identifed with promising activities similar to that observed in vitro for last resort antibiotics, so that the novel compounds enriche the pool of perspec- tive small-molecule antibacterial drug candidates. First draft submitted: 10 January 2020; Accepted for publication: 3 April 2020; Published online: 9 June 2020 Keywords: antibacterial activity • compound evaluation • Enterococcus • lead structure • Staphylococcus • structure-dependent activity Antibacterial therapies have been no real problem for decades as there was a safe number of antibiotics of last resort beside the standard antibiotics in use [1,2]. A misuse of antibiotics in animal husbandry and a prescription of antibiotics in the case of viral infections has led to resistance developments against the antibiotics for almost all clinically relevant bacterial pathogens and thus to a crisis in antibacterial therapies [1,3,4]. However, in case of viral infections, clinicians often prescribe antibiotics also to prevent a bacterial co-infection that often follows. While genetically determined resistance had earlier been restricted to strains of one species, meanwhile mobile genetic elements with resistance determinants have been found with a horizontal gene transfer between different species [5]. Consequently, novel antibacterial agents are needed. They should be novel in structure to prevent an early resistance development based on single mutations or horizontal gene transfer of existing resistance determinants [6]. However, industrial activities to find novel antibiotics presently concentrate on modifications of known antibiotics [4,6,7]. Natural sources for the search of such novel structures have been plants, fungi and bacteria [8–12]. However, isolated novel compounds from such natural sources mostly possess complicated structures and are difficult to be resynthesized in industrial practice [8,13]. The number of innovative small-molecule antibacterials is strongly limited and thus it is a challenge to increase the pool of small-molecule antibacterials which promise lower production costs for a later therapeutical use [13]. We developed novel small-molecule antibacterial agents with a substituted cyclopenta[b]indole core. Cyclopenta[b]indole is a partial structure in a variety of alkaloids with diverse biological activities which result from the different complex structure of the alkaloid compounds [14–18]. Metal-catalysis has been used to build such complex structures of substituted cyclopenta[b]indoles [14]. We developed a simple access Future Med. Chem. (Epub ahead of print) ISSN 1756-8919 10.4155/fmc-2020-0010 C  2020 Newlands Press