recent developments on antimicrobial quinoline...

Recent Developments on Antimicrobial Quinoline Chemistry

Carlos M. Meléndez Gómez1 and Vladimir V. Kouznetsov*2 1Grupo de Investigación en Compuestos Heterocíclicos, Programa de Química, Facultad de Ciencias Básicas, Universidad

del Atlántico, A.A.1890, Barranquilla, Colombia 2Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, A.A. 678,

Bucaramanga, Colombia

Recent developments on antimicrobial quinoline chemistry were shortly reviewed covering six important topics: Historical aspects of the quinoline-based antimicrobial drug development; Increasing resistance problems and reasons for developing new antimicrobial agents; Molecular quinoline-based hybrids in the design and development of novel antimicrobial agents; Structural evolution of the quinolones as effective agents in the treatment of microbial infections and Design and synthesis of new quinoline-based molecules as potential antimycobacterial agents.

Keywords quinoline and quinolone antimicrobial agents, molecular quinoline-based hybrids, antimycobacterial agents

1. General introduction part

The discovery and development of antimicrobial agents that has met with enormous success over the past 50 years provided many classes of natural products and semisynthetic or synthetic compounds (marketing of over 100 antibacterial agents). Among them, quinoline and quinolone derivatives are still an important class of therapeutically useful antibacterial drugs. Quinolines and their derivatives occur in numerous natural products, many of which possess interesting physiological and biological properties. On the other hand, control of deadly infectious diseases (including tuberculosis caused by Mycobacterium tuberculosis) is seriously threatened by multidrug emergence and dissemination of resistant pathogenic microbes. Additionally, patients with AIDS are immune suppressed, and very susceptible to the opportunistic microbial infections that necessitates requiring continuous search into novel classes of antibacterial agents. This search is an area characterized by active investigation with the goal of overcoming the phenomenon of multiple drug resistance (MDR). To resolve these problems some quinoline-based natural products serve as useful models for design and development of new semi-synthetic or synthetic quinoline antimicrobial agents. It is well-known that the quinoline nucleus and its derivatives, chiefly quinolones, play a vital role in the search on wide antibacterial activity spectrum. Structure-activity relationship (SAR) studies revealed that the antimicrobial activity in this heterocyclic class of quinoline molecules depends on the nature of the peripheral substituents and their spatial relationship within the quinoline skeleton. This mini-review aims to resume recent developments on antimicrobial quinoline chemistry focusing on important topics: a). Historical aspects of the quinoline-based antimicrobial drug development; b). Increasing resistance problems and reasons for developing new antimicrobial agents; c). Molecular quinoline-based hybrids in the design and development of novel antimicrobial agents; f). Structural evolution of the quinolones as effective agents in the treatment of microbial infections; e). Design and synthesis of new quinoline-based molecules as potential antimycobacterial agents.

2. Historical aspects of the quinoline-based antimicrobial drug development

Historically, selection for novel antimicrobial compounds has been achieved by testing large libraries of natural products for their ability to kill bacteria and has led to many of the antibiotics used today. Natural quinoline products are not exception. Serving as molecular models quinoline alkaloids of the South American Cinchona sp., Rubiaceae (cinchona alkaloids, quinine, etc.) and acridone alkaloids of the Australian Melicope sp., Rutaceae (melicopine, melicopidine, etc.) motivated the quinoline-based antimicrobial drug development [1, 2]. Quaternary quinoline dyes, nalixidic and oxolinic acids (1,8-naphtyridine and 4-quinolone cores, respectively) were first developed in chemical laboratories. Structural modifications on these cores conducted first to quinolone and then, fluoroquinolone antibacterial agents [3, 4] (Fig. 1). In few time, the quinolone derivatives moved from a relatively small and unimportant group of drugs used predominantly for the treatment of urinary tract infections, to 6-fluoro-4-quinolone molecules having the critical 3-carboxy function with potent activity against a wide spectrum of significant bacterial pathogens such as norfloxacin, pefloxacin and ciprofloxacin that in turn revolutionized the chemistry of fluoroquinolones, developing 6-fluoro-7-piperazinyl-4-quinolones (sparfloxacin, grepafloxacin, gatifloxacin and others). However, there are antimicrobial agents based on 6-flouro-4-oxo-1,8-naphtyridine-3-carboxylic acid core. For example, trovafloxacin possesses this core with 3-azabicyclo[3.1.0]hexyl substituent at the C-7 position. This antibiotic was discovered in the course of a program targeting improved activity compared with ciprofloxacin against Gram-positive aerobic organisms and anaerobes, as well as an extended elimination half-life.

Microbial pathogens and strategies for combating them: science, technology and education (A. Méndez-Vilas, Ed.)

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The huge majority of useful antibacterial agents in this class rely upon variation of peripheral substituents (mainly, C-5, C-6 and C-7 positions of quinoline ring), leaving the 3-carboxy-6-fluoro-4-quinolone core essentially intact. It is known that this type of quinolones rapidly inhibits DNA synthesis by promoting cleavage of bacterial DNA in the DNA-enzyme complexes of type II topoisomerase DNA gyrase and the topoisomerase IV, resulting in rapid bacterial death. The antibiotics based on 7-piperazinyl-4-quinolone core have improved anti-Gram-positive potency compared with ciprofloxacin and have been showed to be active against penicillin-resistant Streptococcus penumoniae. However, some of them launched during recent short period were withdrawn from a number of markets due to unexpected toxicological issues – grepafloxacin (cardiotoxicity), gatifloxacin (glucose homestasis abnormalities), and trovafloxacin (hepatoxicity).

Fig. 1 Historical quinoline-based antimicrobial drugs and their development.

Another interesting antibiotic molecule, delafloxacin, which is now in clinical development, seems to fit a suitable profile, having potent potency against many quinolone-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA) and against Gram-negative bacteria [5]. The preparation of these molecules is considered an easy synthetic problem to resolve although each synthesis of these drugs has own peculiar tactic that in general is based on a classic reaction called Gould-Jacobs synthesis [6]. Comparing to successful development on new fluoroquinolones, research on chemistry of new quinoline-based antimicrobial drugs seems to be underdeveloped. However, certain synthetic small molecules based on quinine core were found to possess broad-spectrum antibacterial activity, which provided a fresh starting point for a potential “old” class of broad-spectrum antibacterial and antimycobacterial agents. Quinine-like molecule Qu1 that acts by inhibition of bacterial gyrase and topoisomerase IV, is efficacious against a strain of flouroquinolone-resistant S. penumoniae in a mouse lung infection model and retains also activity in MRSA [5]. Taking into consideration above-presented facts, the quinoline-based antimicrobial molecules with very attractive properties, combining high potency, a broader spectrum of activity, better bioavailability, oral and intravenous formulations, high serum levels, a large volume of distribution indicating higher concentrations in tissues and a potentially low incidence of side-effects will be certainly designed and developed in near future, and quinoline scaffolds are and will be significant pieces in drug discovery and in optimizing (SAR studies) antibiotics for human use.

3. Increasing resistance problems and reasons for developing new antimicrobial agents

Bacteria have lived on the Earth for several billion years. During this time, they faced in nature a wide range of naturally occurring antibiotics. To stay alive, bacteria can establish antibiotic resistance mechanisms. As a result, it is not surprising that they become resistant to most of the modern antimicrobial drugs used a long time in clinical practice. Particularly, quinoline-based molecules resistance has essentially three types of resistance mechanisms by bacteria to evade the action of quinoline derivatives: 1. There is reticence of access of the drug to the target site, which may occur by reducing entry of the drug into the cell (influx) or by pumping of the drug out of the cell (i.e. efflux); 2. Bacteria can


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very well yield novel enzymes that deactivate and/or modify molecular skeleton of the used drug; 3. The target site can be altered so that the interaction of the drug is reduced in such a way that higher concentration of the drug is required to achieve the same level of inhibition of enzyme activity. Thus, normally susceptible populations of bacteria may develop resistance to antimicrobial agents through mutation and selection, or by acquiring from other bacteria the genetic information that encodes resistance. Accordingly, susceptible bacteria can become resistant to an antimicrobial agent via new spontaneous mutations that are supposed to happen in about one in one million to one in ten million cells. Diverse genetic mutations produce different types of resistance. These acquired resistance genes may allow a bacterium to generate enzymes that deteriorate the antibacterial action of the drug, to express influx/efflux systems and is generally called vertical evolution. Bacteria also accomplish resistance through the acquisition of new genetic material from other resistant organisms. Mechanisms of genetic exchange include conjugation, transduction, and transformation. This acquisition resistance is named horizontal evolution and may take place between strains of the same species or between different bacterial species or genera even families. However, the problem is not only antibiotic resistance but also multidrug resistance. The so-called ‘superbugs’ (organisms that are resistant to most of the clinically used antibiotics) are emerging at a rapid rate [7]. There are severe infections initiated by multidrug-resistant Gram-positive pathogens, which cause high mortality rates especially in the hospital setting. The individual organisms responsible include methicillin-resistant S. aureus (MRSA), vancomycin-resistant MRSA, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant S. pneumoniae. It is known that fluoroquinolone resistance is mainly (but not exclusively) due to mutations in the target enzymes, DNA topoisomerases [8]. In this context, it is important to note that there are also other examples of Gram-positive (Enterococcus and Streptococcus) and Gram-negative pathogens (Klebsiella, Escherichia, Enterobacter, Serratia, Citrobacter, Salmonella and Pseudomonas) in hospitals. It was estimated that these later hospital-inhabiting microbes cause more than 60% of sepsis cases. Additionally, more than 70% of pathogenic bacteria were expected to be resistant to at least one of the currently available antibiotics [9]. Multidrug resistance in bacteria is often initiated by the accumulation of genes, each coding for resistance to a single drug, on R-plasmids, which are genes located on a circular strand of bacterial DNA. The phenomenon of gene acquisition involves gene transfer from some outside source; this source is other bacteria. Bacteria have three methods by which DNA may be transferred from one cell to another; transformation, transduction and conjugation [8]. So, antibiotic resistance plasmids are bacterial extra-chromosomal elements that carry genes conferring resistance to one or more antibiotics. In terms of antibiotic resistance, plasmids play a central role, as the vehicles for resistance gene capture and their subsequent dissemination. Although plasmid host-to-host transfer mechanism is described, further molecular details on how plasmids, or other plasmids with similar properties, transport resistance genes from the original environment to bacteria that infect humans are actually welcome. Thus, the progressive development of multidrug resistance in bacteria (both Gram-negative bacteria and Gram-positive bacteria) to almost all available antimicrobial agents is now very evident. Obviously, bacteria will continue to develop resistance to currently available antibacterial drugs by either new mutations or the exchange of genetic information (old resistance genes into new hosts). To prevent the further increase in multidrug resistant bacteria, the continuation of the molecular resistance mechanism studies are also needed [8]. One added reason for developing new antibacterial drugs is related to their own toxicity that causes side effects in patients. Particularly, the quinolone-base drugs may produce nervousness, tremors and seizures. In view of the above, the design and synthesis of novel antimicrobials is an area of immense significance and continues to attract the attention of increasing number of medicinal chemists. One of the different tactics to struggle against bacterial pathogens is the molecular hybridization approach whose advances will be discussed in the following topics.

4. Molecular quinoline-based hybrids in the design and development of novel antimicrobial agents

Plant secondary metabolites have been used for centuries in traditional medicines and represent a source of potentially active compounds, in which quinoline metabolites are considered promising models for drug development. Indeed, investigations on these alkaloids never stop. Therefore, some fused quinoline vegetable alkaloids were analyzed as antimicrobial agents [10] (the MICs data of the molecules are given in Table 1 and the structures can be seen in Fig. 2). This following information is available: the alkaloids based on quinol-2-one skeleton, edulitine and lunacridine, did not show any antibacterial properties [11, 12], while the pyrano[3,2-c]quinolone derivatives like flindersine and veprisine alkaloids resulted active and selective only against S. aureus (MIC = 125 µg/mL) [13]. Dictamnine alkaloid, which is a direct biosynthetic precursor of γ-fagarine and skimmianine (all are furo[2,3-b]quinoline derivatives), was inactive against any of the tested microorganism [14], whereas γ-fagarine with an extra methoxy group in the C-8 position showed a moderate activity against MRSA, S. aureus and M. luteus (MIC = 500 µg/mL) [15], suggesting that their presence could contribute to the activity, but the skimmianine alkaloid with two methoxy groups in C-7 and C-8 positions exhibited a fair activity only against M. luteus (MIC = 1000 µg/mL) [16], as well as evoxine, a furo[2,3-b]quinoline derivative [17] and ribalinine with dihydropyrano[2,3-b]quinolone core [18]. Nevertheless, the synthetic


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transformations directed to modifying the main core of the natural compounds can be improved their biological properties. The following examples proved the statement. In the case of simple edulitine analogs, trivial chemical transformations improved considerably antibacterial properties: 3-iodo substituted quinol-2-ones 1-3 had enhancements in their antibacterial activity compared to edulitine alkaloid. Noteworthy, the compounds 1,2 possess moderate activity against MRSA, M. luteus and S. aureus, but the quinol-2-one molecule 3 showed a very strong activity against all six microorganisms (Fig. 2). Therefore, the iodine atom at the C-3 position and the absence of substitution in the quinol-2-one skeleton significantly enhanced the properties of these quinol-2-ones compared to natural alkaloid compounds. Table 1 Minimum inhibitory concentrations (MIC, µg/mL) of quinoline derivatives isolated from natural sources.

MIC (µg/mL) Alkaloid Source MRSA S.a M.l B.s E.c S.t

Edulitine Casimiroa edulis >1000 >1000 >1000 >1000 >1000 >1000 Lunacridine Zanthoxylum budrunga >1000 >1000 >1000 >1000 >1000 >1000 Veprisine Vepris louisii >1000 125 >1000 >1000 >1000 >1000 Dictamnine Haplophylhun suaveolens >1000 >1000 >1000 >1000 >1000 >1000 γ-Fagarine Huplophyllum suaveolens

Balfourodendron riedelianum 500 500 500 >1000 >1000 >1000

Skimmianine Haplophylhun suaveolens >1000 >1000 1000 >1000 >1000 >1000 Evoxine Dutaillyea baudouinii >1000 >1000 >1000 >1000 >1000 >1000 Ribalinine Fagaru muyu >1000 >1000 >1000 >1000 >1000 >1000

MRSA: meticillin-resistant S. aureus; S.a: S. aureus; M.l: Micrococcus luteus; B.s.: Bacillus subtilis; E.c: Escherichia coli; S.t.: Salmonella typhimurium.

Fig. 2 Molecular evolution of the quinoline ring. Development of new active antibacterial compounds based on natural models.

From the other hand, veprisine and flindersine alkaloids based on furo[2,3-b]quinoline skeleton had no activity at all, but the N-methylflindersine 4 and 7-hydroxyflindersine 5 showed good results against MRSA, S. aureus and M. luteus (MICs = 125 µg/mL) that indicates that the presence of an N-methyl group or a hydroxyl group in the C-7 position could be enhanced antibacterial properties. The isopropyl side chain of the substituted furoquinoline 6 improved activity towards MRSA, S. aureus and M. luteus compared to dictamine alkaloid, while 2,2-dimethyl dihydropyrano[2,3-b]quinoline 7, derived from ribaniline model showed moderate activity (Fig. 2). These simple quinoline derivatives and others have a long history as antimicrobial agents [19, 20]. Actually, design and preparation of potential quinoline-based antibacterial agents consists partially in a molecular hybridization approach that involves the coupling of two or more groups with relevant biological properties [21, 22]. Thus, quinoline moiety could be coupled (added or replaced) with other heterocycles rings (pyrazole, isoxazole, oxazole, pyridine, pyrimidine, pyrazoline, among others). This approach allowed the construction of new quinoline hybrids libraries with antimicrobial


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properties and with structural diversification in the C-3 position of the quinoline core (Fig. 3) [23, 24]. The following examples proved the approach efficiency. The dihydropyrimidine-chloroquinoline-based hybrids 8 were screened in vitro against microbial strains showing low to moderate antimicrobial properties, in contrast to the quinazolinone-quinoline derivatives 9 that resulted highly active against B. subtilis, S. aureus, S. typhimurium, and P. aeruginosa (Fig. 3).

Fig. 3 Structural diversity oriented toward C-3 position. Quinoline molecular hybrids with potent antimicrobial activity. Pyrazol- and isoxazol-quinoline hybrid libraries showed moderate antimicrobial properties [25, 26]. However, another similar heterocyclic ring, incorporated in quinoline skeleton, as the imidazolinone ring, increased considerably the antimicrobial activity [27]. For example, certain quinoline hybrid molecules of this type were screened showing promising antibacterial properties. In particular, the hydroxyphenyloxadiazoline-quinoline derivatives 10 exhibited a good activity against E. coli and P. aeruginosa cultures (MIC = 25 µg/mL) compared to standard drug ampicillin (MIC = 100 µg/mL and 200 µg/mL, respectively). Triazoles are also an important class of heterocyclic compounds, found in many potent biologically active molecules [28]. Some triazol-quinoline-based hybrids were prepared and tested showing promising antibacterial activities. The phenylthiazol-quinoline compounds 11 were screened against diverse bacterial strains showing moderate antibacterial activities with MICs 10 - 25 mg/mL [29]. Although, in recent years, the majority of pharmaceutical companies have deemphasized their natural product screening efforts natural products, natural products particularly, alkaloids are still very useful and important models in the design and development of antimicrobial agents and chemical modifications (SAR studies) on alkaloid structure can help to find active molecules with antimicrobial properties.

5. Structural evolution of the quinolones as effective agents in the treatment of microbial infections

As it was mencioned in the topic 2, fluoroquinolone molecules exhibit high potency against a broad range of pathogens [30] and its important biological evolution has been accompanied by structural changes in the C-7 position of the 6-fluoro-3-carboxyquinolin-4-one ring [31]. The incorporation of a fluorine atom in the C-7 position allowed increasing significantly in antimicrobial activity [32, 33] to discover potent drug, ciprofloxacin (Fig. 1). Further studies for developing new quinolone agents were based on chemical modifications of C-7 substituents in the same ciprofloxacin core, using aromatic substitution reactions [34] (Fig. 4). There are intersesting and important adavances in this theme. Some azetidine-quinolone derivatives 12 presented moderate antimicrobial activity, while the thioazetidin-pyrimidine derivatives possess potent activity against S. aureus (MIC = 0.063 µg/mL), E. faecalis (MIC = 0.25 µg/mL), M. catharralis (MIC = 0.063 µg/mL), H. influenzae (MIC ≤ 0.008 µg/mL), comparable to the reference drugs (levofloxacin, ciprofloxacin and gatifloxacin) [35]. It was also found that the pyrrolidine moiety introduction in the ciprofloxacin core conducted to generate new pyrrolidine-quinolone-based molecules 13 with important MICs values


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against ciprofloxacin-resistant S. pneumonia and S. aureus strains and some isothiazolidinone-quinolone derivatives 14 resulted highly active against resistant S. aureus [36]. Thus, 6-flouro-3-carboxyquinolin-4-one molecules linked or substituted with these heterocyclic rings have shown to be promising antibacterial agents [37].

N

OR2

R3

OH

O

Ciprofloxacin

NS

N

N

R1R4

NN

R1 =

R3 =R2= F

R1 =

R2 = R4= F

S. aureus (0.063 µg/mL)E. faecalis (0.25 µg/mL)M. catharralis (0.063 µg/mL)H. inf luenzae (0.008 µg/mL)

12

NH2N

NCH

R1 = R2= HR4 = OCH3

R1 =13

S. aureus res.(0.008 µg/mL)S. pneumoniae res.(0.5 µg/mL)

R2 = FR4 = OCH2CHCH3

S. aureus res.(0.008 µg/mL)S. pneumoniae res.(0.125 µg/mL)

N

N

[a-] =

[a-] =

R1 =R2 = F

R1 =R2 = F

SNH

O

S. aureus (0.015 µg/mL)S. pyogenes (0.059 µg/mL)M. catharralis (0.0037µg/mL)

SNH

O

S. aureus (0.016 µg/mL)S. pyogenes (0.25 µg/mL)M. catharralis (0.0081µg/mL)

14

NHN

O

O R1 = ArR2 = F

S. aureus (10 µg/mL)S. epidermis (10 µg/mL)B. cereus (12 µg/mL)E. coli (14 µg/mL)K. pneumoniae (14 µg/mL)

15

NN

SS

O2N

S. aureus (0.5 µg/mL)E. epidrmidiss (0.03 µg/mL)

R1 =R2 = F16

N

SBr

HO

S. aureus (0.03 µg/mL)E. epidrmidiss (0.06 µg/mL)B. subtitlis (0.03 µg/mL)

R1 =R2 = F17

C-3 Substitution

H

N-Modification

Fig. 4 Biological evolution and structural diversification. Ciprofloxacin derivatives as promising antimicrobial agents. Furthermore, several piperazine-quinolone-based hybrids were constructed to antimicrobial test; in particular, new molecules 15 from this type of hybrids have shown to be promising agentes against S. aureus, S. epidermidis, M. luteus, B. cereus, E. coli , K. pneumonia strains, possessing better MICs values than those reference drug (ciprofloxacin, MIC ≥ 25 µg/mL) in all strains studied [38]. This fact suggests the significance of both fluorine atom and piperazine ring presence in the 6-flouro-3-carboxyquinolin-4-one core for the antimicrobial properties. Additionally, it was noted that the piperazinyl moiety can be easily coupled with diverse heterocyclic groups allowing chemical functionalization [39]. This is the case of the thiadiazol-quinolone hybrids 16 that exhibited potent activity against S. aureus (MIC = 0.5 µg/mL) and S. epidermis (MIC = 0.03 µg/mL) strains [40] and new oxime derivatives based on thiophen-quinolone skeleton were highly active against Staphylococcus species, with comparable or superior activities to the reference drugs. Among them, the hybrids 17 stand out showing a remarkable activity against S. aureus (MIC = 0.03 µg/mL) [41] (Fig. 4). The above-described examples prove that both molecular hybridization approach and chemical modifications could improve considerably antibacterial properties of quinoline molecules.

6. Design and synthesis of new quinoline-based molecules as potential antimycobacterial agents

Tuberculosis (TB) that is caused by the bacterium Mycobacterium tuberculosis (Mtb) remains the most deadly bacterial disease in the world: one-third of the world population is infected with Mtb and hence at risk of developing active TB [42]. In 2011, nearly 9 million people around the world became sick with tuberculosis, and there were 1.4 million TB-related deaths [43, 44]. On the other hand, the rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic [45]. Cost of diagnosing and treating of these cases was estimated at $16.9 billion, with annual costs increasing from $700 million in 2009 to $4.4 billion in 2015 [46]. Current TB chemotherapy is centered on the combination of four “old” first-line anti-TB drugs (isoniazid - INH, pyrazinamide - PZA, rifampicin - RMP, and ethambutol - EMB) that act on their each specific cellular targets inhibiting them and have not a quinoline skeleton in their molecular structures (Fig. 5). There are several major problems related with the currently available TB treatment. First, the duration and complexity of treatment result in no adherence to treatment. Second, adverse events in response to anti-TB drugs are common and contribute to the problem of no adherence. Third, the increasing incidence of multidrug-resistant TB


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(MDR; resistance to at least RMP and INH) and extensively drug-resistant (XDR; MDR resistance plus resistance to fluoroquinolones or aminoglycosides) is a serious concern. Alarmingly, approx. 425,000 MDR-TB cases occur annually worldwide, representing nearly 5% of the world’s annual TB burden. Moreover, the diagnosis of MDR-TB requires sophisticated laboratories with highly skilled microbiologists. Patients with MDR-TB require a much longer treatment period, usually 24 months, compared with the 6-8 months required for drug-susceptible TB [47].

Fig. 5 Agents used in current anti-TB managements. Thus, there is an urgent demand for breakthroughs in the discovery of new anti-TB drugs possessing novel modes of action and targets [48, 49] and satisfying following specific criteria: a) be active against drug-resistant forms of Mtb acting upon different molecular targets from the current drugs; b) be part of a multidrug regime utilizing different metabolic pathways to the other drugs to avoid drug-drug interactions; c) have effectiveness in co-administration with antiviral agents used to treat AIDS due to high mortality level associated HIV/AIDS problems; d) be effective for treating pediatric TB, which is an important proportion of the global TB burden, and finally, e) be inexpensive for the developing countries that have the vast majority of all TB cases [50, 51]. Therefore, development of the current clinical portfolio is partially dedicated to the repurposing of existing antibiotics alongside current TB drugs as part of new multidrug regimes. Some of these antibiotics have fluoroquinolones skeleton, for ex., gatifloxacin (GAT), moxifloxacin (MXF) and levofloxacin (LVF) (Fig. 6).

Fig. 6 Quinoline-based agents in clinical evaluation. In preliminary studies it was found that these fluoroquinolones exhibited excellent early bactericidal activity, approaching that for INH and a recent phase II trial to investigate whether MXF could replace EMB in combinations revealed that although the MXF regimes showed more frequent sputum conversion at 4 weeks, the success of the treatments provided identical outcomes after 2 months. Additionally, two distinct phase III clinical trials evaluating the success of a 4 month regime that contains either one of the fluoroquinolones, GAT or MXF, are actually ongoing [50, 52]. Moreover and encouragingly, the development pipeline now contains new quinoline-based anti-TB drug, bedaquiline (BQ, TMC207, R207910) was approved recently [53]. This drug pipeline for TB is the best it has ever been, with 10 drugs in clinical testing, belongs to completely new classes of antibiotics with no reported resistance, and represent an unprecedented opportunity to improve treatment for MDR-TB. Bedaquiline is the first member of the new class of diarylquinoline compounds, more exactly, 6-bromo-2-methoxyquinoline 3-substituted with an aminobutyl chain, in which phenyl, α-naphthyl and hydroxyl groups are present. BQ works by inhibiting Mtb ATP synthase, depriving the


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bacterium of energy and causing it to die [53]. By contrast, INH and EMB disorder the formation of the cell wall, although via different mechanisms; PZA is hydrolyzed into pyrazinoic acid, which may affect bacterial fatty acid synthesis or protein synthesis; and RMP inhibits RNA synthesis (Fig. 5, 6). BQ is a single enantiomer of a compound with two chiral centers with the carbon bearing the phenyl substituent of the R configuration and with the carbon bearing the hydroxyl group of the S configuration. Very interestingly, this quinoline molecule was selected as the lead compound in the series after a mouse infection study showed it was the only compound in a series of three tested to have significant activity against both drug-susceptible and drug-resistant strains of Mtb, exhibiting MIC values of 30 -120 ng/mL, equal to or lower than INH and RMP. Noteworthy, bedaquiline has been approved for tuberculosis, but phase III trials have not yet begun because it was approved only under an accelerated approval pathway. Moreover, the TB Alliance is now developing new combination regime with BQ, PZA and a nitroimidazole antibiotic PA-824 that inhibits cell wall biosynthesis, and BQ, the antimycobacterial agent clofazimine and MFX (a repurposed antibacterial agent that inhibits DNA gyrase and is not approved for TB) [54]. Thus, the approval of bedaquiline is being seen as a starting point for a new era of TB therapy, not the end of the road. But although this drug represents one of the most encouraging of the new drug candidates for the TB treatment, there remains a critical issue. BQ is rapidly metabolized by cytochrome P-450 isoform 3A4, an isoform that is strongly unregulated with the use of RMP, possibly the single most important agent used for first line chemotherapy [55]. Additionally, another critical issue consists in the chemical complexity of the BQ scaffold those synthetic preparation requires chiral HPLC resolution at the last synthetic phase of five-step synthesis. Nevertheless, Mtb, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A vital question is how robust are existing approaches to discovering new anti-TB drugs and what procedures could be taken to reduce the prolonged clinical development of new drugs [56]. It is known that the poor efficiency of identifying new anti-TB drugs by screening pharmaceutical library collections has been linked to the limited chemical diversity within these collections [57]. Taking into consideration that malarial quinoline-based drugs (such as quinine, chloroquine, melfloquine, etc.) possess moderate biological activity against TB and quinoline nature of the BQ, then diversely-substituted quinoline skeleton could be a good start point for the development of new anti-TB agents. This success in the development of leading BQ based on quinoline skeleton and at the same time, high metabolic instability and complex chemical structure and synthesis of the BQ prompt many chemists to start new anti-TB drug design and investigation looking for new quinoline molecules type A-D (Fig. 7). Anti-TB mefloquine-isoxazole hybrids, like molecule A were designed and prepared considering that anti-TB agents must be synthetically feasible, without side effects, and have physicochemical properties allowing oral administration; moreover, they must shorten the duration of the treatment. This lead compound served in the synthesis of new 5-[(E)-2-arylethenyl]-3-isoxazolecarboxylic acid alkyl ester derivatives (without quinoline skeleton!) but with excellent activity (submicromolar MIC) against both replicating Mtb and nonreplicating persistent form and devoid of apparent toxicity to Vero cells. These interesting results were obtained by Kozikowski and co-workers [58-62].

Fig. 7 Search for diversely-substituted quinoline skeletons with anti-TB activity. It is well-known that antimicrobial activity against Mycobacterium species depends on how efficiently the cell wall constitutes an efficient permeability barrier; log D or clog P values turned out to be very important physicochemical properties in the search of new anti-TB agents. clog P parameter is a key parameter of the “Lipinski’s rule of 5” that indicates at the membrane permeability potency of the molecules. Similar physicochemical parameter, log D parameter can predict gastro intestinal track absorption and lipophilic properties as it is a pH dependent function. The following examples testify the importance of physicochemical properties of tested molecules.


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4-Quinolinylhydrazones, like INH-quinolone hybrid molecule C (Fig. 7) showed marked anti-TB activity possessing a good MIC (0.78 µg/mL), but poor selectivity for mycobacteria (SI = 6.67). Among prepared and tested 66 compounds the molecule B resulted more active having the high clog P (7.9) that means that it is a good lipophilic compound [63]. A series of 26 new substituted quinoline-3-carbohydrazides with (3R)-3-amino-N,N-dimethyl-4-(phenylthio) butanamidyl moiety such as molecule C was also designed, prepared and tested for their in vitro antituberculosis activity against Mbt H37Rv, M. smegmatis, and M. fortuitum. Among them seven molecules exhibited significant MIC (1 - 10 µg/mL), when compared with first-line drugs INH and RIF [64]. Noteworthy, the best molecule C, ideally suited for further modifications to obtain more efficacious and potent anti-TB drugs, showed lower clog P parameter (5.3) than the BQ (7.2). New chloroquine-thiazolidinone hybrids, like molecules D (Fig. 7) resulted less promising as anti-TB agents exhibiting a moderate activity (16-64 µg/mL) against various mycobacteria species. It was noted that chemical nature of C-2 aryl substituent (2-thienyl, 2-furyl, 3,4-dimethoxyaryl or 3-methoxy-4-hydroxyaryl) on the thiazolidinone ring and the length of the aminoalkyl side chain of these hybrids (2, 3 or 4 carbons) have a slight influence over the antituberculosis activity [65]. In an attempted to observe a possible correlation between the calculated distribution coefficients at pH 7.4 and pH 6.0 (log D7.4 and log D6.0 parameters), and the found MICs for the tested compounds log D values were calculated. Obtained values of tested compounds D presented log D6.0 values from 1.23 to 3.27 as well as log D7.4 from 2.44 to 4.52 that indicates high to moderate GI track absorption (pH 3-7) and lipophilic properties. However, calculated values of studied anti-TB reference drugs (INH, RMP, and BQ) varied too much to be compared with those for tested compounds. For example, INH is a highly hydrophilic molecule (log D6.0 and log D7.4 = -1.51 and -1.52) while new drug BQ is a very lipophilic compound (log D6.0 and log D7.4 = 7.34 and 3.88), and RMP is the case of border-line (log D6.0 and D7.4 = 1.80 and 1.80). The structural, chemical and functional analyses of the BQ are important starting points to shed some light on the origin of its antimycobacterial activity by addressing which of the parts of this molecule is more relevant as a pharmacophore for the anti-TB activity. With this idea, Chattopadhyaya and co-workers divided this molecule into four hemispheres and synthesized new series of compounds based on North-East (NE) and South-East (SE) hemispheres of BQ drug [66, 67] (Fig. 8).

Fig. 8 Search for diversely-substituted quinoline skeletons with anti-TB activity. Based on molecular dissection (NE and SE hemisphere modifications) and molecular modelling and docking studies of the BQ, authors prepared a new series of substituted quinolines 18 in which the hydroxyl group (NE part) and the naphthalene moiety (SE part) are absent; instead of that, different amine groups are present. The side chain with the N,N-dimethyl amino terminal of BQ was removed. The key reason of all these changes was to improve physicochemical parameters of quinoline molecules, which may lead to an enhanced fit into the binding site. The antimycobacterial activity of these compounds was evaluated in vitro against Mtb H37Rv for nine consecutive days upon a fixed concentration (6.25 µg/mL) at day one in Bactec assay and compared to untreated TB cell culture as well as one with INH drug treated counterpart, under identical experimental conditions. The obtained results indicated that among new twenty quinoline molecules 18 (not shown in Fig. 8) there were four active compounds 18a-d that exhibited 92–100% growth inhibition of mycobacterial activity, with MIC of 6.25 µg/mL [66]. These compounds have respective


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clog P values 4.69, 4.96, 7.43 and 6.19. It should be noted that clog P parameter of the molecule 18c (7.43) is very similar to those of BQ (7.20). Replacing the methoxy group at the C-2 position with fluoro-aryloxy fragment having heterocyclic amine moieties and bromine atom at the C-6 position with 3-phenyltriazolyl ring, additional series were generated furnishing different compounds 19,20 [67] (Fig. 8). By use the same biological protocol it was found that substituted quinoline molecules 19a, 20a and 20b inhibited Mtb H37Rv up to 96%, 98% and 94% respectively, at a fixed concentration of 6.25 µg/mL. Possessing high clog P values 8.40, 7.17 and 7.18, respectively, these compounds are very lipophilic molecules. 3-Benzyl-2-[4-fluoro-2-(1-imidazol-1-yl-ethyl)-phenoxy]-6-(4-phenyl-[1,2,3]triazol-1-yl)-quinoline 19a resulted the best molecule with MIC of 3.125 µg/mL and with clog P values (8.40) higher than those of BQ (7.20). The above-mentioned quinoline derivatives 18-20 revealed a great potential to serve as promising candidates for further development of antimycobacterial agents with improved potency. Chattopadhyaya’s works showed the importance of chemical modifications of the BQ model that could help in improving BQ-based compounds against TB infection. Additionally, it was demonstrated that docking studies are a useful tool for identifying critical binding sites of the target ATP synthase. Noteworthy, antibacterial drugs are unique in a set of physicochemical properties, such as higher molecular weights, lower lipophilicities (log D, log P, clog P) and increased topological polar surface areas when compared to drugs for human host targets [68], but there are some exceptions. Thus, to better understanding of the antibacterial physicochemical property space diverse synthetic and natural molecules are urgently needed. With no defined optimal physicochemical properties for anti-TB drugs, chemistry for the discovery of new scaffolds should be less restricted. Nevertheless, the strategies to search for new anti-TB drugs involve screening molecular both natural and synthetic libraries and the identification of possible targets crucial to the microorganism with the succeeding design of new molecules. In this later regard, chemical biology has played an important role in this respect in understanding the mechanisms of killing of various bacteria. Thus, the mechanisms involved in cell death and survival must be studied in detail to prospectively select targets for structure-guided drug design [69]. The TB epidemic has been further fuelled by emergence of MDR-TB and XDR-TB strains and it will be difficult to achieve global control of this epidemic without efficient coordination of governmental and non-govermental organizations. Although success in the development of leading agents and TB vaccine pipeline [70], more vaccines and drugs from different class are needed.

7. Concluding remarks

Although the past decade has seen tremendous progress in many of the different aspects of the drug-discovery process, infectious diseases will continue to emerge and re-emerge, leading to unpredictable epidemics and difficult challenges to public health and to microbiology and allied sciences. The success of the discovery and development of antimicrobial agents is influenced by many factors; the full range of biological, enzymological, chemical and structural tools to be arranged, greatly increasing the chances that a drug candidate can be identified and developed.

Acknowledgements Financial support from Patrimonio Autónomo Fondo Nacional de Financiamiento para la Ciencia, la Tecnología y la Innovación, Francisco José de Caldas, contract RC-0572-2012, is gratefully acknowledged. C.M.M.G. thanks COLCIENCIAS for the fellowship.

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