Periodontal diseases are highly prevalent with about 30% of the human population being affected worldwide, have considerable impact on individuals and society, and are costly to treat. The cost of dental care is the fourth highest of all diseases and consuming between 5 and 10% of all healthcare resources (Batchelor, P. British Dental Journal 2014, 217, 405-409). Representative population studies show that periodontal diseases are widespread and their prevalence has been increasing since 1997 (Micheelis, W. et al. Vierte Deutsche Mundgesundheitsstudie (DMS IV), Deutscher Arzte-Verlag, Koln, 2006). Amongst the adult population in Germany, 52.7% were found to be affected by moderately severe and 20.5% by severe forms of pe odontitis. The health insurance expenditure in Germany for the direct treatment of pehodontitis amounted to about EUR 1 .1 billion (Statistisches Bundesamt, 2008), not including the costs incurred by secondary diseases.

Pehodontitis is a general term describing inflammation condition of the periodontal apparatus which is caused by multi-bacterial induction and has strong relations to various systemic diseases, such as

cardiovascular diseases, rheumatoid arthritis, chronic obstructive pulmonary disease and Alzheimer's disease.

The currently established therapy of pehodontitis, according to the recommendations of the German Society Of Dental, Oral And Craniomandibular Sciences, is generally performed by manual supra and subgingival debridement (removal of the bacterial plaques) along with the application of antiseptic substances (daily disinfection by mouth washes), which disintegrates the entire oral biofilm and provides an opportunity for recolonization by potential pathogens. Furthermore, adjuvant systemic broad-spectrum antibiotic therapy is applied in advanced disease forms. The latter also leads to a non-selective destruction of the biofilm and has to be administered in high doses and over a prolonged pe od of time in order to reach sufficient therapeutic levels at the particular site of action, i.e. the gingival pocket. Standard adjuvant therapy of pehodontitis involves, for instance, systemic administration of doxyciclin (per os) 1 x 200 mg/die for 1 day and 2 x 100 mg/die for further 18 days (Wissenschaftliche Stellungnahme: Adjuvante Antibiotika in der Parodontitistherapie, Deutsche Gesellschaft fur Zahn- Mund- und Kieferheilkunde, DZZ 2003). As a result, resistance development in oral pathogens is observed. Further, the microbiome in the patient's intestine is destroyed, which leads to a loss of metabolic support, immune modulation, and enables recolonization by potential pathogens.

The presence of periodontopathogenic bacteria varies among pehodontitis patients. Nevertheless, the occurrence of certain bacterial species in the subgingival plaques has been found to be closely associated with the etiology of periodontal diseases (Socransky et al., Journal of Clinical Periodontology, 1998, 25, 134-144).

Thus, there is a high demand for the development of a new treatment for pehodontitis and related conditions which is capable of targeting pathogens which induce a periodontal disease, while preferably substantially preserving the rest of the naturally occurring biofilm. Such treatment would provide significant improvement to patients and healthcare systems.

PROBLEMS TO BE SOLVED BY THE INVENTION

In view of the above, the present invention aims at the object of identification, purification and isolation of a novel therapeutic target protein which can be used for identifying inhibitors capable of targeting pathogens which induce a periodontal disease.

A further object of the present invention is to provide an antibody which recognizes said therapeutic target protein.

A further object of the present invention is to provide a method for identifying an inhibitor of said therapeutic target protein.

A further object of the present invention is to provide an inhibitor of said therapeutic target protein, and a pharmaceutical composition comprising such inhibitor. Said inhibitor should be preferably a selective inhibitor, i.e. selectively killing or selectively inhibiting the growth of (a) target bacte al pathogen(s) while being substantially inactive towards other bacte al and/or human protein targets.

A further object of the present invention is to provide a method for treatment of the human or animal body, and/or a compound or a pharmaceutical composition for use in such method.

A further object of the present invention is to provide a method for therapy or prophylaxis of a bactehal infection, and/or a compound or a pharmaceutical composition for use in such method, preferably by selectively killing or selectively inhibiting the growth of the pathogenic bactehal species.

A further object of the present invention is to provide a method for therapy or prophylaxis of an acute, chronic or recurrent periodontal disease and/or a compound or a pharmaceutical composition compound for use in in such method.

In the methods for treatment according to the above objects, the route of administration should be preferably topical administration or systemic administration, and the methods are preferably non-surgical methods.

SUMMARY OF THE INVENTION

As a solution to the above-formulated problems, the present invention provides a bactehal glutaminyl cyclase (bacQC), wherein the bacQC is a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, and an amino acid sequence having a sequence identity of 80% or more to any one of SEQ ID NO: 1 , SEQ ID NO: 2 and SEQ ID NO: 3.

The present invention further provides an antibody which recognizes the bacQC as defined above. The present invention further provides a method for identifying an inhibitor of the bacQC as defined above, the method comprising:

(a) providing a composition comprising a substrate of the bacQC and the bacQC;

(b) providing a candidate compound;

(c) contacting the candidate compound with the composition;

(d) monitoring the catalytic activity of the bacQC;

(e) classifying the candidate compound as an inhibitor of the bacQC based on the effect of the candidate compound on the catalytic activity of bacQC, wherein a candidate compound that reduces the catalytic activity of the bacQC is classified a bacQC inhibitor.

The present invention further provides a compound according to the following Formula I,

Formula I

its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof,

wherein Ar, L, R^ , R^, R3, and R^ are defined according to the appended claims.

The present invention further provides a pharmaceutical composition comprising the compound as defined above and a pharmaceutically acceptable excipient.

The present invention further provides a bacQC inhibitor, i.e. a compound identified by the above method for identifying an inhibitor of the bacQC and/or a compound according to the above Formula I, and/or a pharmaceutical composition as defined above for use in a method for treatment of the human or animal body; for use in a method for therapy and/or prophylaxis of a bacterial infection; and for use in a method for therapy and/or prophylaxis of an acute, chronic or recurrent periodontal disease.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows an amino acid sequence alignment of human QC (hQC, SEQ ID NO: 4) and putative bacterial QC from P. gingivalis (PgQC, SEQ ID NO: 1 ) (A), and an amino acid sequence alignment of further putative QC P. intermedia (PiQC, SEQ ID NO: 2) and T. forsythia (TfQC, SEQ ID NO: 3)) and P. gingivalis (PgQC, SEQ ID NO: 1 ) (B).

Fig. 2 shows SDS-PAGE of purified recombinant putative bacterial QCs expressed in E. coli

Rosetta(DE3)pLysS.

Fig. 3 shows Lineweaver-Burk plots for PgQC (A), PiQC (B) and TfQC (C) catalyzed cyclization of H-Gln-AMC.

Fig. 4 shows exemplary v/S characteristics, Lineweaver-Burk and Eadie-Hofstee plots for PgQC-catalyzed cyclization of H-Gln-AMC in the presence of compound MWT-S-00431 .

Fig. 5 shows the pH dependency of PgQC activity (A), PiQC activity (B) and TfQC activity (C).

Fig. 6 shows the influence of ionic strength on bacterial QC activity.

Fig. 7 shows the inhibition of bacterial QC activity by different metal chelators: EDTA (A), dipicolinic acid (B), and 1 ,10-phenantroline (C).

Fig. 8 shows UV-Spectra of recombinant bacterial QCs.

Fig. 9 shows a CD spectroscopic analysis of recombinant bacterial QCs.

Fig. 10 shows the thermal stability of recombinant bacterial QCs: PgQC (A), PiQC (B), and TfQC (C). Fig. 11 shows PhoA activity in permeabilized E. coli CC1 18 pGP1 -2 cells expressing seqPgQC-'PhoA fusion proteins.

Fig. 12 shows the specifity of polyclonal antiserum against (A) PgQC and (B) TfQC and PiQC.

DETAILED DESCRIPTION OF THE INVENTION

Socransky et al. (Journal of Clinical Periodontology, 1998, 25 134-144) described that the occurrence in subgingival plaques of a so-called "red complex" consisting of the tightly related group Tannerella forsythia, Porphyromonas gingivalis and Treponema denticola relates strongly to clinical measures of periodontal disease, and in particular to pocket depth and bleeding on probing.

A further related complex (so-called "orange complex") includes members of the Fusobacterium nucleatum/periodonticum subspecies, Prevotella intermedia, Prevotella nigrescens and Peptostreptococcus micros. Colonization of healthy periodontal sites by members of the "orange complex" was found to correlate with the occurrence of gingivitis. The bacteria of the "orange complex" furthermore promote the colonization by bacteria of the "red complex", which in turn are associated with deep pockets and chronic periodontitis.

Bacteria of the "red complex" and the "orange complex" secrete a variety of virulence factors. For instance, it was found that P. gingivalis secretes cysteine proteases such as gingipain, P. intermedia secretes salivary IgA proteases, and T. forsythia secretes glycosidases.

The present inventors found surprisingly that about 80% of the secreted proteins bearing a signal peptide in the secretome of the oral pathogens P. gingivalis, T. forsythia, and P. intermedia are cleaved at a Xaa-Gln peptide bond by a signal peptidase. The N-termini of the released proteins contain a pGlu-residue. This implies the existence of glutaminyl cyclases which seem to be essential for growth protein translocation across outer membrane and the growth of said periodontal pathogens.

Glutaminyl cyclases (QCs) (EC 2.3.2.5) are acyltransferases that catalyze the cyclization of N-terminal glutaminyl residues of proteins to pyroglutamate (pGlu) under release of NH3, thus modifying the N-terminus of the peptides:

Gln pGlu

Two types of QCs (Type I and Type II) have been defined so far. Type I QCs were found in plants and in several pathogenic bacteria and human parasites (Huang et al., J. Mol. Biol. 2010, 401, 374-388). Papaya QC (pQC) is the best-known Type I QC. This enzyme was first discovered in the latex of the tropical plant Carica papaya (Messer, M. Nature 1963, 197, 1299). The enzyme exhibits catalytic activity over a broad pH range (pH 3.5-1 1 ). X-ray crystallographic analyses revealed that pQC is a hatbox-shaped molecule, consisting of a five-bladed β-propeller traversed by a central channel (Wintjens, R., Belrhali, H., Clantin, B., Azarkan, M., Bompard, C, Baeyens-Volant, D., Looze, Y., and Villeret, V. J. Mol. Biol. 2006, 357, 457^70). pQC contains a zinc ion but is not inhibited at all by heterocyclic chelators (Zerhouni et al, . Biochim. Biophys. Acta 1998, 1387, 275-290), and it is therefore assumed that the zinc has only a structural and stabilizing function. pQC is highly resistant to proteolytic, chemical, and thermal denaturations (Wintjens et al., Zerhouni et al.)

Type II QCs were mainly identified in the neuroendocrine tissues of mammals. Among Type II QCs, the human QC (hQC) is the most extensively studied one, which is known to be important in the maturation of numerous neuropeptides and cytokines in their secretory pathways. In contrast to Type I QCs, hQC is quite susceptible to chemical and thermal denaturation. Schilling et al., 2003 (J. Biol. Chem. 2003, 278, 49773-

49779) have shown that hQC was significantly unstable above pH 8.5 and below pH 6.0. hQC adopts an α/β topology (Huang et al. Proc. Natl Acad. Sci. USA, 2005, 102, 131 17-13122) and was identified as a metalloenzyme, as suggested by the time-dependent inhibition by the heterocyclic chelators. Inactivated enzyme can be fully restored by the addition of Zn^+ in the presence of equimolar concentrations of EDTA (Schilling et al., 2003). Thus, Type II QCs are metal-dependent transferases, suggesting that the active site bound metal (Zn^+) is essential for the catalytic activity, in contrast to the Type I QCs, wherein zinc has only a structural and stabilizing function.

In summary, Type I QCs are generally found in plants, several bacteria and protozoa; they exhibit β-propeller structures; high resistance against proteolysis, heat, and acid; the optimal catalytic activity is at pH 3.5-1 1 ; and possess a structural Ca^+ Zn2+ ion.

In contrast, Type II QCs are mainly found in vertebrates; they exhibit α/β-topologies; low resistance against proteolysis, heat, and acid; the optimal catalytic activity is at pH 6.0-8.0; and there is catalytically essential Zn^+ ion. Thus, Type II glutaminyl cyclases are zinc-dependent acyltransferases.

The present inventors surprisingly found that Type II QCs (in the following: "bacQC") are expressed in the oral pathogens P. gingivalis, T. forsythia, and P. intermedia.

The primary structure of the QC protein from P. gingivalis (PgQC, SEQ ID NO: 1 ) has a 25% identity to human QC (hQC, SEQ ID NO: 4). Furthermore, QC from P. intermedia (PiQC, SEQ ID NO: 2) and T. forsythia (TfQC, SEQ ID NO: 3) were identified, which share an identity to PgQC of 42% and 49%, respectively. Further experimental evidence shows that these enzymes indeed belong to the Type II QC family, as confirmed inter alia by pH and ionic strength dependency of the bacQC activity (Example 4), the inhibition of the QC activity by metal chelators (Example 5), the folding patterns of all three proteins suggesting an α/β topology as indicated by the CD spectroscopic analysis (Example 6), and their thermal stability (Example 7).

The present inventors found that bacQCs are expressed in and are essential for the growth of 2 out of 3 periodontitis-causing bacterial species of the "red complex", as well as at least one bacterial species of the "orange complex", and are therefore of crucial importance for as a target for the development of a therapeutic inhibitor with antibiotic properties for the treatment of periodontitis diseases and conditions.

Therapeutic Target Proteins (bacQC)

The present invention provides a bacterial glutaminyl cyclase (bacQC), wherein the bacQC is a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, and an amino acid sequence having a sequence identity of 80% or more to any one of SEQ ID NO: 1 , SEQ ID NO: 2 and SEQ ID NO: 3. bacQCs according to the present inventions can be identified, isolated and purified as described in Example 1 , and can be used to identify inhibitors capable of selective targeting of periodontitis-inducing pathogens as further described in Examples 2 and 3.

For the purposes of comparing two or more amino acid sequences, the degree of identity between two amino acid sequences (percentage of "sequence identity") can be determined by conventional methods, for example, by means of standard sequence alignment algorithms known in the state of the art, such as, for example BLAST (Altschul S.F. et al. J Mol Biol. 1990, 215(3), 403-10).

Antibodies

The present invention further provides an antibody which recognizes a bacterial Type II glutaminyl cyclase (bacQC). The bacQC recognized by the antibody according to the present invention is preferably a polypeptide comp sing an amino acid sequence selected from the group consisting of SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, and an amino acid sequence having a sequence identity of 80% or more to any one of SEQ ID NO: 1 , SEQ ID NO: 2 and SEQ ID NO: 3.

In one embodiment, the antibody is a polyclonal antibody. In another embodiment, the antibody is a monoclonal antibody.

In one further embodiment, the antibody exhibits high affinity and specificity for PgQC (SEQ ID NO: 1 ) as compared to any one of PiQC (SEQ ID NO: 2), TfQC (SEQ ID NO: 3) and/or hQC (SEQ ID NO: 4). In another embodiment, the antibody exhibits high affinity and specificity for PgQC (SEQ ID NO: 1 ) as compared to any one of PiQC (SEQ ID NO: 2), TfQC (SEQ ID NO: 3), and/or hQC (SEQ ID NO: 4).

In another embodiment, the antibody exhibits high affinity and specificity for PiQC (SEQ ID NO: 2) as compared to any one of PgQC (SEQ ID NO: 1 ), TfQC (SEQ ID NO: 3), and/or hQC (SEQ ID NO: 4).

In another embodiment, the antibody exhibits high affinity and specificity for TfQC (SEQ ID NO: 3) as compared to any one of PgQC (SEQ ID NO: 1 ), PiQC (SEQ ID NO: 2), and/or hQC (SEQ ID NO: 4).

In yet another embodiment, the antibody is preferably a chimeric, humanized or human antibody.

Method for Identifying an Inhibitor

The present invention further provides a method for identifying an inhibitor of the bacQC comp sing the following steps a)-e):

a) providing a composition comphsing a substrate of the bacQC and the bacQC;

b) providing a candidate compound;

c) contacting the candidate compound with the composition;

d) monitoring the catalytic activity of the bacQC;

e) classifying the candidate compound as an inhibitor of the bacQC based on the effect of the candidate compound on the catalytic activity of bacQC, wherein a candidate compound that reduces the catalytic activity of the bacQC is classified a bacQC inhibitor.

According to an embodiment of the invention, said composition is an aqueous solution, preferably comphsing suitable buffer and/or salt components. Said substrate is preferably a peptide or peptide dehvative comphsing a glutamine residue at its N-terminus. Said substrate is preferably labeled, more preferably isotopically labeled, most preferably a fluorogenic substrate. The fluorogenic substrate preferably undergoes a change in fluorescence intensity after being converted in the course of a reaction catalyzed by a bacQC.

A suitable fluorogenic substrate for monitoring bacQC activity is H-Gln-AMC, as described in Schilling, S., Hoffmann, T., Wermann, M., Heiser, U., Wasternack.C., and Demuth, H.-U. Anal. Biochem. 2002, 303, 49-56 (Schilling et al., 2002):

bacQC pGAP

H-Gln-R > pGlu-R + NH3 > pGlu + R†

R = 7-amino-4-methylcoumarin pGAP = pyroglutamyl aminopeptidase

The candidate compound can be contacted prior to, simultaneously with or after the addition of the remaining components of the composition of step a). The candidate compound is preferably provided in solution, more preferably as a DMSO solution.

The conversion of the substrate is monitored over time, e.g., by monitoring the emission of the fluorophore generated by the cleavage of a fluorogenic substrate. bacQC activity can be determined from a standard curve of the AMC under assay conditions.

The bacQC catalytic activity can be determined using different concentration of substrate, bacQC and/or candidate compound. Suitable measures for the bacQC catalytic activity are, e.g., inhibitory constants (Kj), 50% residual activity (RA) in the presence of a given concentration of a candidate compound, and/or IC50 values.

bacQC Inhibitors

The present invention further provides a bacQC inhibitor, which is a compound identified by the method for identifying an inhibitor of the bacQC according to the present invention and/or a compound according to any one of the following aspects <1 >-<20>.

A compound according to the following Formula I,

Formula I

its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof,

wherein Ar is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;

wherein L is selected from the group consisting of single bond, -CR^(R^)-, -CR^(R^)-CR^(R^)-, and -C(R5)=C(R6)-;

wherein R^ , R2, R3, R^, R5 R6, R?, and R^ are the same or different from each other and are independently selected from the group consisting of H, F, CI, Br, I, OH, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroalkyl, and optionally substituted heteroaryl;

wherein in each pair of groups R ' /R2, R3/R4, R5/R6 and R7/R8, the two groups can be optionally joined together to form a carbocyclic or a heterocyclic ring, or can optionally represent =0.

<2> The compound according to aspect <1 >, wherein , R^, R3 , and R^ are the same or different from each other and are independently selected from H, OH, optionally substituted C _Q alkyl, and optionally substituted C _Q heteroalkyl.

<3> The compound according to aspect <1 > or <2>, wherein each of R^ and R^ is H.

<4> The compound according to any one of aspects <1 > to <3>, wherein R^ and R^ together represent =0.

<5> The compound according to any one of aspects <1 > to <4>, wherein R3 and R4 are independently selected from group consisting of H, optionally substituted C-| _6 alkyl, and optionally substituted C-|_6 heteroalkyl.

<6> The compound according to aspect <5>, wherein R3 is methyl.

<7> The compound according to aspect <5> or <6>, wherein R4 IS selected from the group consisting of H and methyl.

<8> The compound according to aspect <7>, wherein each of R3 and R4 IS methyl.

<9> The compound according to any one of aspects <1 > to <7>, wherein each of R3 and R4 is H.

<10> The compound according to aspect <1 >, wherein R^ and R^ are joined together to form a carbocyclic or a heterocyclic ring.

<1 1 > The compound according to any one of aspects <1 > to <5>, wherein R3 and R4 are joined together to form a carbocyclic or a heterocyclic ring.

<12> The compound according to aspect <10> or <1 1 >, wherein R^ and R^ or R3 and R4 are joined together to form a heterocyclic group represented by the following Formula II:

Formula II.

<13> The compound according to any one of aspects <1 > to <12>, wherein L is a single bond.

<14> The compound according to any one of aspects <1 > to <12>, wherein L is selected from the group consisting of -CR5(R6)-, -C(R5)=C(R6)- and -CR5(R6)-CR7(R8)-.

<15> The compound according to aspect <14>, wherein R^, R^, R^ and R^ are the same or different from each other and are independently selected from group consisting of H, OH, optionally substituted C _Q alkyl, and optionally substituted C _Q heteroalkyi.

<16> The compound according to aspect <15>, wherein each of R^, R >, RJ and R^ is H.

<17> The compound according to any of aspects <1 > to <16>, wherein Ar is selected from the group

consisting of aryl, alkoxyaryl, carboxyaryl, cyanoaryl, haloaryl, hydroxyaryl, alkoxyheteroaryl, cyanoheteroaryl, haloheteroaryl, heteroarylaryl, hydroxyheteroaryl and carboxyheteroaryl, each of which can be optionally substituted.

<18> The compound according to any of aspects <1 > to <17>, wherein Ar is selected from the group

consisting of: 1 ,3-benzodioxol-5-yl, 2,3-dichlorophenyl, 2,3-dihydro-1 ,4-benzodioxin-6-yl, 3-chloro-5- methoxyphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3,4,5-trifluorophenyl, 3,5- dichlorophenyl, 4-(benzyloxy)phenyl, 4-[2-(morpholin-4-yl)ethoxy]phen-1 -yl, 4-butoxyphenyl, 4- chlorophenyl, 4-fluoro-3-methoxyphenyl, 4-fluorophenyl, 4-methoxyphenyl, biphenyl-3-yl, naphthalen- 2-yl, and phenyl.

<19> The compound according to any one of aspects <1 > to <17>, wherein said substituted aryl is

represented by one of the following structures Ar-I to Ar-VI,

For On-ll-lll On On-IV-V-VI On

wherein:

R^ 2 is independently selected from the group consisting of H, F, CI, Br, I, OH, CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyi, and optionally substituted heteroaryl;

R13 is independently selected from the group consisting of H, CI, Br, I, OH, CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyi, and optionally substituted heteroaryl;

R 4 is independently selected from the group consisting of H, F, CI, Br, I, OH, CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyi, and optionally substituted heteroaryl;

R is independently selected from the group consisting of H, CI, Br, I, OH, CN, optionally substituted alkyi, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyi, and optionally substituted heteroaryl;

R16 is independently selected from the group consisting of H, F, CI, Br, I, OH, CN, optionally substituted alkyi, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyi, and optionally substituted heteroaryl;

wherein any two groups of to can optionally be joined together to form a carbocyclic or a heterocyclic ring; and

wherein at least one of R^ to R^ is not H.

<20> The compound according to any one of aspects <1 > to <17>, wherein said substituted aryl is

represented by one of the following structures Ar-VII to Ar-XIV,

Ar-Ar VII-VIII-IX Ar Ar-X-Ar-Ar XI XII

wherein:

R12 is independently selected from the group consisting of F, CI, Br, I, OH, CN, optionally substituted alkyi, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyi, and optionally substituted heteroaryl;

R13 is independently selected from the group consisting of F, CI, Br, I, OH, CN, optionally substituted alkyi, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyi, and optionally substituted heteroaryl;

R14 is independently selected from the group consisting of F, CI, Br, I, OH, CN, optionally substituted alkyi, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyi and optionally substituted heteroaryl;

R is independently selected from the group consisting of F, CI, Br, I, OH, CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyl, and optionally substituted heteroaryl;

R l b is independently selected from the group consisting of F, CI, Br, I, OH, CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyl, and optionally substituted heteroaryl;

is independently selected from the group consisting of F, CI, Br, I, OH, CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyl, and optionally substituted heteroaryl;

each R18 is independently selected from the group consisting of H, F, CI, Br, I, OH, CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroalkyl, and optionally substituted heteroaryl; and n is selected from 0, 1 , 2, 3, 4, 5 and 6; and

any two groups of R^ to R^ can optionally be joined together to form a carbocyclic or a heterocyclic ring.

The expression "alkyl" as used herein, unless specifically limited, denotes a C-].^ alkyl group, suitably a C^ _8 alkyl group, e.g. C<\ _Q alkyl group, e.g. C^ .4 alkyl group. Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, iso-butyl, sec-butyl and tert-butyl), pentyl (e.g. n-pentyl), hexyl (e.g. n-hexyl), heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl). The term "alkyl" also comprises cycloalkyi groups. The expression "cycloalkyi", unless specifically limited, denotes a 03.^ 0 cycloalkyi group (i.e. 3 to 10 ring carbon atoms), more suitably a C3 g cycloalkyi group, e.g. a 03.5 cycloalkyi group. Exemplary cycloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A most suitable number of ring carbon atoms is three to six.

The expression "heteroalkyl", unless specifically limited, refers to an alkyl group wherein one or more carbon atoms, preferably 1 , 2 or 3, are replaced by heteroatoms selected from N, S and O.

The expressions "carbocyclyl" and "carbocyclic", unless specifically limited, denote any ring system in which all the ring atoms are carbon and which contains between three and twelve ring carbon atoms, suitably between three and ten carbon atoms and more suitably between three and eight carbon atoms. Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic, and tricyclic ring systems, in particular monocyclic and bicyclic ring systems. Other carbocylcyl groups include bridged ring systems (e.g. bicyclo[2.2.1 ]heptenyl). A specific example of a carbocyclyl group is a cycloalkyi group. A further example of a carbocyclyl group is a cycloalkenyl group.

The expression "aryl", unless specifically limited, denotes a CQ_<\ 2 aryl group, suitably a CQ_<\ Q aryl group, more suitably a CQ_Q aryl group. Aryl groups will contain at least one aromatic ring (e.g. one, two or

three rings). An example of a typical aryl group with one aromatic ring is phenyl. An example of a typical aryl group with two aromatic rings is naphthyl.

The expressions "heterocyclyl" and "heterocyclyc", unless specifically limited, refer to a carbocyclyl group wherein one or more (e.g. 1 , 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O. A specific example of a heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g. 1 , 2 or 3, particularly 1 or 2, especially 1 ) ring atoms are replaced by heteroatoms selected from N, S or O. Exemplary heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two hetero atoms include morpholine and piperazine. A further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1 , 2 or 3, particularly 1 or 2, especially 1 ) ring atoms are replaced by heteroatoms selected from N, S and O. An example of such a group is dihydropyranyl (e.g. 3,4-dihydro-2H-pyran-2-yl-).

The expression "heteroaryl", unless specifically limited, denotes an aryl residue, wherein one or more (e.g. 1 , 2, 3, or 4, suitably 1 , 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O, or else a 5-membered aromatic ring containing one or more (e.g. 1 , 2, 3, or 4, suitably 1 , 2 or 3) ring atoms selected from N, S and O. Exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene); and six membered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl). Exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1 -yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine, pyrazine). Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1 ,2,3-triazole and 1 ,2,4-triazole. Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole. Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl), benzofuran, benzthiophene, quinoline, isoquinoline, indazole, benzimidazole, benzothiazole, quinazoline and purine.

The expressions "alkoxyaryl", "carboxyaryl", "cyanoaryl", "haloaryl", "hydroxyaryl" and "heteroarylaryl", unless specifically limited, denote an aryl residue which is substituted by at least one alkoxy, carboxy, cyano, halo, hydroxy and heteroaryl group, respectively.

The expressions "alkoxyheteroaryl", "carboxyheteroaryl", "cyanoheteroaryl", "haloheteroaryl" and "hydroxyheteroaryl", unless specifically limited, denote a heteroaryl residue which is substituted by at least one alkoxy, carboxy, cyano, halo, and hydroxy group, respectively.

The expression "alk", for example in the expressions "alkoxy", "haloalkyl" should be interpreted in accordance with the definition of "alkyl". Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy (e.g. n-octoxy). Exemplary haloalkyl groups include fluoroalkyl e.g. CF3; exemplary haloalkoxy groups include fluoroalkyl e.g. OCF3.

The term "halogen" or "halo" comprises fluorine (F), chlorine (CI), bromine (Br) and iodine (I).

The term "optionally substituted" refers to optional substitution by one or several groups independently selected from C<\ _Q alkyl, C<\ _Q heteroalkyl, C<\ _Q carbocyclyl, heterocyclyl, and heteroaryl group, each of which may be substituted by one or several halogen atoms and/or hydroxyl groups; a halogen atom, cyano group, and hydroxyl group.

Stereoisomers

All possible stereoisomers of the claimed compounds are included in the present invention.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base, or by salt formation with an optically active base, such as quinine, quinidine, quinotoxine, cinkotoxine, (S)-phenylethylamine, (1 R,2S)-ephedrine, (R)-phenylglycinol, (S)-2-aminobutanol, followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

Polymorph Crystal Forms, Solvates, Hydrates

Furthermore, some of the individual crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. In view of the close relationship between the free compounds and the compounds in the form of their salts, hydrates or solvates, whenever a compound is referred to in this context, a corresponding salt, solvate or polymorph is also intended, provided such is possible or appropriate under the circumstances.

Tautomers

As used herein, the term "tautomer" refers to the migration of protons between adjacent single and double bonds. The tautomerization process is reversible. Compounds described herein can undergo any possible tautomerization that is within the physical characteristics of the compound.

Pharmaceutically Acceptable Salts

As used herein, the term "pharmaceutically acceptable" embraces both human and veterinary use. For example, the term "pharmaceutically acceptable" embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care.

Salts, hydrates and solvates of the compounds of Formula I and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable. However, salts, hydrates and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as

intermediates in the preparation of other compounds and their pharmaceutically acceptable salts, hydrates and solvates.

Suitable salts according to the invention include those formed with either organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochlo c, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or naphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1 - or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalenes-acrylic), benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1 ,4-benzenediacrylic), isethionic acids, perchloric, propionic, glycolic, hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic, saccharinic and trifluoroacetic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and A/-methyl-D-glucamine.

All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of the present invention.

Pharmaceutical Compositions

The pharmaceutical composition according to the present invention comprises a compound as described above and a pharmaceutically acceptable excipient.

As used herein, the term "pharmaceutical composition" is intended to encompass a product comprising the claimed compounds in the therapeutically effective amounts, as well as any product that results, directly or indirectly, from combinations of the claimed compounds. As used herein, the term "excipient" refers to a carrier, a binder, a disintegrator and/or a further suitable additive for galenic formulations, for instance, for liquid oral preparations, such as suspensions, elixirs and solutions; and/or for solid oral preparations, such as, for example, powders, capsules, gelcaps and tablets. Carriers, which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, granulating agents, dyes, and coloring agents.

Therapeutic Applications

The present invention provides a bacQC inhibitor compound, i.e. a compound identified by the method for identifying an inhibitor of the bacQC according to the present invention and/or a compound according to any one of the above aspects <1 >-<20>, or a pharmaceutical composition as described above for use in a method for treatment of the human or animal body. The present disclosure also provides a method for treatment of the human or animal body wherein the method comprises administration of a therapeutically effective amount of said compound or composition to a subject in need thereof.

The present invention further provides a bacQC inhibitor compound or a pharmaceutical composition as described above for use in a method for therapy or prophylaxis of a bacterial infection. The present

disclosure also provides a method for therapy or prophylaxis of a bacterial infection wherein the method comprises administration of a therapeutically effective amount of said compound or composition to a subject in need thereof. The bacte al infection is preferably caused by a bacte um that expresses a Type II bactehal glutaminyl cyclase (bacQC). More preferably, the bactehal infection is caused by a bactehum selected from the group consisting of the genera Porphyromonas, Prevotella and Tannerella, preferably selected from the group consisting of the species Porphyromonas gingivalis, Prevotella intermedia and Tannerella forsythia,.

The bacQC inhibitor compound or the pharmaceutical composition used in the methods according the present invention preferably selectively kill or selectively inhibit the growth of a bactehum selected from the group consisting of the genera Porphyromonas, Prevotella and Tannerella, preferably selected from the group consisting of the species Porphyromonas gingivalis, Prevotella intermedia and Tannerella forsythia, within a biofilm, whereas the remaining bacteria within the biofilm preferably remain essentially unaffected (i.e. are killed or their growth is inhibited to a significantly smaller extent). Said biofilm is preferably a complex biofilm, more preferably a naturally occurring biofilm, and even more preferably a naturally occurring oral biofilm.

The present invention further provides a bacQC inhibitor compound or a pharmaceutical composition for use in a method for therapy or prophylaxis of an acute, chronic or recurrent periodontal disease or condition. The major categories of periodontal diseases and conditions are classified in the groups of dental plaque-induced gingival diseases, chronic periodontitis, aggressive periodontitis, periodontitis as a

manifestation of systemic diseases, necrotizing periodontal diseases, abscesses of the periodontium, periodontitis associated with endodontic lesions, peri-implant mucositis, peri-implantitis, and endodontic infections. In the present invention, the acute, chronic or recurrent periodontal disease is preferably selected from the group consisting of dental plaque-induced gingival diseases, chronic periodontitis, aggressive periodontitis, periodontitis as a manifestation of systemic diseases, necrotizing periodontal diseases, abscesses of the periodontium, periodontitis associated with endodontic lesions, peri-implant mucositis, peri-implantitis, and endodontic infections. The present disclosure also provides a method for therapy or prophylaxis of an acute, chronic or recurrent periodontal disease which is preferably selected from the group consisting of dental plaque-induced gingival diseases, chronic periodontitis, aggressive periodontitis, periodontitis as a manifestation of systemic diseases, necrotizing periodontal diseases, abscesses of the periodontium, periodontitis associated with endodontic lesions, peri-implant mucositis, peri-implantitis, and endodontic infections, wherein the method comprises administration of a therapeutically effective amount of a bacQC inhibitor compound or a pharmaceutical composition according to the present invention to a subject in need thereof. Further acute, chronic or recurrent periodontal diseases are deschbed, e.g., in Armitage, A. Ann Periodontol 1999, 4, 1 -6.

In one embodiment of the present invention, the inhibitor compound or the pharmaceutical composition according to the present invention is preferably used in any of the methods deschbed above, wherein the route of administration is topical administration, and/or wherein the method is a nonsurgical method. In another embodiment, the inhibitor compound or the pharmaceutical composition according to the present invention is preferably used in any of the methods deschbed above, wherein the route of administration is systemic administration, and/or wherein the method is a nonsurgical method.

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, therapy, prophylaxis, observation or experiment.

The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

EXAMPLES

Example 1 : Identification and Preparation of putative bacterial glutaminyl cyclases (bacQC) a) Identification

Bioinformatics analysis of the secretome of the oral pathogens P. gingivalis, T. forsythia, and P. intermedia (http://www.oralqen.lanl.gov/) showed that about 80% of the secreted proteins bearing a signal peptide are cleaved at a Xaa-Gln peptide bond by the signal peptidase. The N-termini of the released proteins contain a pGlu-residue. This implies the existence of glutaminyl cyclases which seem to be essential for growth protein translocation across outer membrane and the growth of periodontal pathogens.

Fig. 1 shows an amino acid sequence alignment of human QC (hQC, SEQ ID NO: 4) and putative bacterial QC from P. gingivalis (PgQC, SEQ ID NO: 1 ) (A), and an amino acid sequence alignment of further putative QC P. intermedia (PiQC, SEQ ID NO: 2) and T. forsythia (TfQC, SEQ ID NO: 3) and P. gingivalis (PgQC, SEQ ID NO: 1 ) (B). Putative PgQC possesses a 25% identity to human QC. Furthermore, putative TfQC exhibits a 49% identity to PgQC and QC from P. intermedia possess a 42% identity to PgQC. Grey underlined cysteine residues reflects disulfide bridges in hQC which is missing in PgQC. Bold sequences in human QC reflects highly conserved residues of Type II QC. Grey sequences described putative signal sequences of PgQC and hQC Furthermore the typical metal binding motif Asp-Glu-His is presented in bold and underlined letters. A putative metal binding motif was also identified in TfQC and PiQC (B, bold letters). The alignments were prepared using program Clustal Omega at EMBL-EBInet; (*) indicates positions which have a single, fully conserved residue, (:) indicates conservation between groups of strongly similar properties, (.) indicates conservation between groups of weakly similar properties (http://www.ebi.ac.uk/Tools/msa/clustalo/).

BLAST analysis revealed an open reading frame (ORF) encoding putative QC protein in P. gingivalis

(WP_005874301 ). The primary structure of this putative QC protein shows a 25% identity to human QC. Furthermore, putative QC proteins were also identified in the genome of the oral pathogens P. intermedia (WP_014709208) and T. forsythia (WP_014225037) which shares a 42% or 49% identity to putative QC from P. gingivalis (Fig. 1 ). As shown by the amino acid alignment, conserved residues of human QC seem to be different in bacterial QCs from those conserved cysteine residues which form disulfide bound in human and other Type II QCs are presumably not presence in all three putative bacterial QC. However, highly conserved metal binding motif Asp144, Glu184 (Asp) and His322 of Type II QC (Wintjens et al., 2006) seem to be present in bacterial putative QC which could represent the catalytic center. The primary structures of these proteins may provide an indication that these proteins are actual QCs.

b) Preparation

Fig. 2 shows SDS-PAGE of purified recombinant putative bacterial QCs expressed in E. coli Rosetta(DE3)pLysS and purified as described in detail below. Therefore, 30 μg purified protein were loaded to 12% SDS-PAGE and visualized by coomassie staining, lane 1 , PageRuler Broad Range unstained

(Thermofisher Scientific), lane 2, HisPgQC, lane 3, HisPiQC and lane 5, HisTfQC. All three putative bacterial QCs possess a theoretical molecular mass of = 37 KDa.

Host strains and media

E. coli strain DH5 or XL-1 blue (Stratagene) were used for cloning procedures. E. coli

Rosetta(DE3)pLysS (Novagene) was used for protein expression. The alkaline phosphatase activity assay was performed in the CC1 18 pGP1 -2 strain (Tabor, S. and Richardson, C. C. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 1074-1078; Manoil, C, J. J. Mekalanos and Beckwith, J. J. Bacteriol. 1990, 172(2), 515-518). All E. coli strains were grown in Luria-Bertani medium as indicated at 20°C, 30°C or 37°C. Antibiotics (ampicillin [50 to 125 mg/liter], chloramphenicol [15 to 30 mg/liter], and kanamycin [25 mg/liter]) were added where appropriate. For preparation of solid media 1 .5 % agar (Roth) was added to corresponding broth.

Molecular cloning of plasmid vectors encoding the bacterial QCs

All cloning procedures were performed applying standard molecular biology techniques. For protein expression, open reading frames (ORFs) of PgQC (SEQ ID NO: 1 , putative QC from P. gingivalis), PiQC (SEQ ID NO: 2 putative QC from P. intermedia) and TfQC (SEQ ID NO: 3, putative QC from T. forsythia) were amplified using synthesized DNA sequences purchased from Eurofins Genomics as templates in a PCR to introduce a Nhe\ INde\ restriction site essential for direct cloning into the vector pET28a(+) (Novagen). For the construction of a PgQC-'PhoA fusion protein, putative pgQC with predicted signal sequence was subcloned into pET26b(+) via Nhe\IXho\ restriction site using primer pair seqPgQC Nde\ (forward) and seqPgQC Xho\ reverse. Furthermore, pgQC with native signal sequence including a ribosome binding site of a pET26b(+) vector was amplified using primer pair seqPgQC RBS Not\ (forward) and seqPgQC Xba\ (reverse) to clone into the phoA expression vector pECD637. All Primers for cloning were purchased from Metabion and described in Table 1 .

Table 1: Oligonucleotides used for cloning ofbacQC constructs

SEQ ID NO: Primer Sequence (5'→ 3')

5 pgQC Nde \ (forward) AAA CAT ATG AAC GGC AAT AAC ACA AGT GAA

6 pgQC Nhe \ (reverse) TCA TTT GCT AGC GTG TGA AGC GGC TTT

7 p/'QC A/del (forward) TTT CAT ATG AAA GGA AAA TCG TCT AAC

8 p / ' QC and Nhe \ (reverse) TAC ATG ATG CTA GCT TAA CTG AGC AC

9 tfQC Nde\ (forward) TCA CAT ATG GGT CAG AAA AAT ACG ACA

10 tfQC Nhe \ (reverse) TCA ATG CTA GCT TAT TTC TTA TAA ATC AC

CAT ATG AAA AAA CTG ATA AGA GGA ACA ACA

1 1 seqPgQC Nde\ (forward) GCA GCC TTT CTA CTG GCT GCT ACA CTC TCT

GCC TGC AAC GGC AAT AAC ACA AGT GAA ACG

12 seqPgQC Xho\ (reverse) TTT CTC GAG GTG TGA AGC GGC TTT CAC

seqPgQC RBS Not
13 CGG CCG TGG CTA AGA AGG AGA

(forward)

14 seqPgQC Xbal (reverse) TTT TCT AGA GTG TGA AGC GGC TTT CAC

Expression of bacterial QC as His Tag fusion protein or as 'PhoA fusion protein

The expression vector pET28a(+): .pgQC was transformed in E. coli Rosetta(DE3)pLysS. Bacteria were grown in Luria-Bertani medium containing kanamycin (25 pg/ml) and chloramphenicol (15 pg/ml) at 37°C

until the cell density reached an OD 600 ~ 0.6. The cultures were induced with 0.4 mM isopropyl β-D-l -thiogalactopyranoside and a 2% (v/v) ethanol volume was added followed by an incubation time for 16 h at 20°C. Cultures were harvested by centrifugation at 4°C and 3900 g for 30 min and cell pellets were storage at -20°.

CLAIMS

A compound according to the following Formula I,

Formula I

its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof,

wherein Ar is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;

wherein L is selected from the group consisting of single bond, -CR^(R^)-, -CR^(R^)-CR^(R^)- and -C(R5)=C(R6)-;

wherein R^ , R2, R3, R^, R5 R6, R? and R^ are the same or different from each other and are independently selected from the group consisting of H, F, CI, Br, I, OH, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroalkyl and optionally substituted heteroaryl;

wherein within each pair of groups R ' /R2, R3/R4, R5/R6 and R7/R8, the two groups can be optionally joined together to form a carbocyclic or a heterocyclic ring, or can optionally represent =0.

The compound according to claim 1 , wherein R^ , R2, R3 and R4 are the same or different from each other and are independently selected from H, OH, optionally substituted C _Q alkyl and optionally substituted C _Q heteroalkyl.

The compound according to claim 1 or 2, wherein each of R^ and R2 is H.

The compound according to any one of claims 1 to 3, wherein R^ and R2 together represent =0.

5. The compound according to any one of claims 1 to 4, wherein R3 and are independently selected from group consisting of H, optionally substituted C<\ _Q alkyl and optionally substituted C<\ _Q heteroalkyl.

6. The compound according to claim 5, wherein R^ is methyl.

7. The compound according to claim 5 or 6, wherein R4 is selected from the group consisting of H and methyl.

8. The compound according to claim 7, wherein each of R^ and R^ is methyl.

9. The compound according to any one of claims 1 to 7, wherein each of R^ and R^ is H .

10. The compound according to any one of claims 1 to 9, wherein R^ and R^ are joined together to form a carbocyclic or a heterocyclic ring.

1 1 . The compound according to any one of claims 1 to 5, wherein R^ and R^ are joined together to form a carbocyclic or a heterocyclic ring.

12. The compound according to claim 10 or 1 1 , wherein R^ and R^ or R^ and R^ are joined together to form a heterocyclic group represented by the following Formula II:

Formula II.

13. The compound according to any one of claims 1 to 12, wherein L is a single bond.

14. The compound according to any one of claims 1 to 12, wherein L is selected from the group consisting of -CR5(R6)-, -C(R5)=C(R6)- and -CR5(R6)-CR7(R8)-.

15. The compound according to claim 14, wherein R^, R >, R? and R^ are the same or different from each other, and are independently selected from group consisting of H, OH, optionally substituted C _Q alkyl and optionally substituted C _Q heteroalkyl.

16. The compound according to claim 15, wherein each of R^, R >, RJ and R^ is H .

17. The compound according to any one of claims 1 to 16, wherein Ar is selected from the group consisting of aryl, alkoxyaryl, carboxyaryl, cyanoaryl, haloaryl, hydroxyaryl, alkoxyheteroaryl, cyanoheteroaryl, haloheteroaryl, heteroarylaryl, hydroxyheteroaryl and carboxyheteroaryl, each of which can be optionally substituted.

18. The compound according to any one of claims 1 to 17, wherein Ar is selected from the group

consisting of: 1 ,3-benzodioxol-5-yl, 2,3-dichlorophenyl, 2,3-dihydro-1 ,4-benzodioxin-6-yl, 3-chloro-5- methoxyphenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl, 4-(benzyloxy)phenyl, 4-[2-(morpholin-4- yl)ethoxy]phen-1 -yl, 4-butoxyphenyl, 4-fluoro-3-methoxyphenyl and naphthalen-2-yl.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient.

20. A compound according to any one of claims 1 to 18 or a or a pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in a method for treatment of the human or animal body.

21 . A compound according to any one of claims 1 to 18 or a or a pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in a method for therapy and/or prophylaxis of a bacterial infection.

22. The compound according to any one of claims 5 to 9 or a pharmaceutical composition comprising the compound according to any one of claims 5 to 9 and a pharmaceutically acceptable excipient for use in a method for therapy and/or prophylaxis of a bacterial infection.

23. The compound according to any one of claims 1 to 18 or the pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in the method according to claim 21 , wherein the bacterial infection is caused by a bacterium that expresses a bacterial glutaminyl cyclase (bacQC), wherein the bacQC is a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, and an amino acid sequence having a sequence identity of 80% or more to any one of SEQ ID NO: 1 , SEQ ID NO: 2 and SEQ ID NO: 3.

24. The compound according to any one of claims 1 to 18 or the pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in the method according to any of claims 21 to 23, wherein the bacterial infection is caused by a bacterium selected from the group consisting of Porphyromonas gingivalis, Prevotella intermedia and Tannerella forsythia.

25. The compound according to any one of claims 1 to 18 or the pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in the method according to claim 24, wherein the compound or the composition selectively inhibits the growth of said bacterium within a biofilm.

26. A compound according to any one of claims 1 to 18 or a pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in a method for therapy or prophylaxis of an acute, chronic or recurrent periodontal disease which is preferably selected from the group consisting of: dental plaque-induced gingival diseases, chronic periodontitis, aggressive periodontitis, periodontitis as a manifestation of systemic diseases, necrotizing periodontal diseases, abscesses of the periodontium, periodontitis associated with endodontic lesions, peri-implant mucositis, peri-implantitis and endodontic infections.

27. The compound according to any one of claims 1 to 18 or the pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in the method according to any of claims 21 to 26, wherein the route of administration is topical administration.

28. The compound according to any one of claims 5 to 9 or the pharmaceutical composition comprising the compound according to any one of claims 5 to 9 and a pharmaceutically acceptable excipient for use in the method according to any of claims 21 to 26, wherein the route of administration is topical administration.

29. The compound according to any one of claims 1 to 18 or the pharmaceutical composition according to any one of claims 1 to 18 for use in the method according to any of claims 21 to 26, wherein the method is a nonsurgical method.

30. The compound according to any one of claims 5 to 9 or a pharmaceutical composition comprising the compound according to any one of claims 5 to 9 and a pharmaceutically acceptable excipient for use in the method according to any of claims 21 to 26, wherein the method is a nonsurgical method.