Quinoline and quinolone dimers and their biological activities: An overview
Xue-Mei Chu1, Cong Wang2, Wen Liu1, Li-Li Liang1, Kai-Kai Gong3, Cheng-Ying Zhao4, Kun-Lai Sun1,*
Abstract:
Quinoline and quinolone motifs which act as structural subunits of more complex natural products are ubiquitous in nature, and they are useful pharmacophores which play a pivotal role in drug development. Compared with the corresponding monomeric compounds, the dimers usually exhibited some unique properties, so dimers have caused great interests in recent years. Quinline and quinolone dimers possess various biological properties such as antibacterial, anticancer, antimalarial and antitubercular activities, and some of them which are exemplified by piperaquine have already used in clinical practice. Numerous quinline and quinolone dimers have been synthesized and screened for their in vitro and in vivo biological activities, and some of them exhibited promising potency. Therefore, quinline and quinolone dimers have the potential for clinical deployment in the control and eradication of various diseases. This review covers the recent advances of quinline and quinolone dimers as bioactive substances. The structure-activity relationship was also discussed to provide an insight for rational designs of more active quinline by piperaquine have already used in clinical practice inspires more research towards quinline and quinolone dimers [13].
In the past three decades, numerous quinline and quinolone dimers have been synthesized and screened for their in vitro and in vivo biological activities, and some of them exhibited considerable potency. This review covers the recent advances on quinline and quinolone dimers as potential antibacterial, anticancer, antimalarial and antitubercular agents. The structure-activity relationship (SAR) is also discussed to provide an insight for further rational designs of more active quinline and quinolone dimers.
Keywords: Quinoline, quinolone, dimer, antibacterial, anticancer, antimalarial, antitubercular, structure-activity relationship
2. Anti-bacterial activity
Bacterial infections which are responsible for the majority of hospital-acquired infections have already put a heavy burden on the global health system [19], and the widely spread of resistance bacteria poses an ever-growing health concern [20]. It’s estimated that around 700,000 deaths occurred annually which attribute to the drug-resistant pathogens, and the number may increase to 10 million in the year of 2050 if current trends continue. All above facts are creating an urgent need to develop new antibacterials with excellent activity against both drug-sensitive and drug-resistant pathogens.
Quinoline and quinolone derivatives especially fluoroquinolone antibiotics are one of the most common used drugs in antiinfective chemotherapy for the treatment of various bacterial infections, but bacteria have already developed resistance to this kind of antibiotics [21]. Quinoline and quinolone dimers may have the potential to overcome the resistance since increasing molecular mass and bulkiness of substituent quinoline and quinolone core is not a barrier to penetration, so quinoline and quinolone dimers worth to be exploited.
Pharmacokinetic studies revealed that the aryl groups at N-1 position could enhance the bioavailability of the quinolone-3-carboxylic acids, and the substituent at N-1 position having a STERIMOL length of 0.42 nm proved to be important for the activity [22]. Based on that, a series of quinolone dimers 1 (Figure 2) with the linkers ethylene and 1,2-cyclohexyl at N-1 position were screened for their in vitro antibacterial activities against Escherichia coli (E. coli) ATCC 8739 and Staphylococcus aureus (S. aureus) ATCC 6538 by Chepyala et al. [23]. All dimers (diameter of inhibition zone of 0-22 mm at 50 and 100 µg/disc for E. coli and S. aureus, respectively) were less potent than the reference ciprofloxacin (inhibition zone: 36 and 38 mm at 50 and 100 µg/disc for E. coli and S. aureus, respectively), and more than a half of them were inactive against S. aureus. SAR indicated that carboxylic acids (R = H) were generally more active than the corresponding ethyl esters, and introduction of fluorine atom ant C-8 position (R2) could enhance the activity to some extent.
Quinolone(nalidixic acid/oxolinic acid)-fluoroquinolone(ciprofloxacin/norfloxacin) bis-conjugates 2 and 3 (Figure 2) with amino acid linkers may decrease degradation of the antibiotic and consequently increase concentration at the target site, so their antibacterial properties were investigated employing Gram-positive bacteria (S. aureus and S. pyogenes) and Gram-negative bacteria (Salmonella typhi and Pseudomonas aeruginosa/P. aeruginosa) by Panda et al. [24]. All bis-conjugates 2 and 3 showed weak to moderate activities against the tested four strains with MIC of 3.3-2116.5 µM, and almost all of them were less active than the parents. The SAR indicated that bis-conjugates were more active against Gram-positive bacteria than Gram-negaitive strains. Compounds 2b (MIC: 7.8 µM) and 2f (MIC: 3.3 µM) exhibited promising antibacterial properties against Gram-positive S. pyogenes and S. aureus, respectively, whereas the precursors nalidixic acid, oxolinic acid, ciprofloxacin and norfloxacin revealed weak to moderate antibacterial properties (MIC: 74.6-3,914.3 µM, respectively). Moreover, compounds 3g,h (MIC: 7.6 and 7.4 µM) were no inferior to the four references (MIC: 7.2-10.3 µM) against Gram-negative Salmonella typhi.
A series of symmetric dimers of ciprofloxacin, norfloxacin and pipemidic acid, as well as asymmetric ciprofloxacin-norfloxacin and ciprofloxacin-pipemidic acid dimers were screened for their antibacterial activities against five drug-resistant strains of S. aureus SA 1199 (a wild-type isolate, resistant to fluoroquinolone), SA 1199-3 (a laboratory-derived mutant of SA 1199 that inducibly overexpresses norA and has no DNA gyrase or topoisomerase IV mutations), SA 1199B (a derivate of SA 1199 that constitutively overexpresses norA and harbors a topoisomerase IV A subunit substitution (A116E) known to correlate with raised fluoroquinolone MICs), methicillin-resistant S. aureus (MRSA) isolate and vancomycin-insensitive S. aureus (GISA) [25,26]. Compared with the parents ciprofloxacin, norfloxacin and pipemidic acid (MIC: 0.125->16 µg/mL), all symmetric and asymmetric dimers (MIC: <0.03-1 µg/mL) showed enhanced potency against SA 1199, SA 1199-3, SA 1199B and MRSA strains. Moreover, all the parents ciprofloxacin, norfloxacin and pipemidic acid (MIC: >16 µg/mL) were inactive against GISA, whereas some of dimers displayed moderate activities with MIC in a range of 2 to 8 µg/mL. These results demonstrated that both the linker between the two quinolone motifs and the monomer used to construct the dimer play a pivotal role in dictating activity. In general, the asymmetric dimers were more active than the symmetric dimers, and for symmetric dimers, ciprofloxacin dimers were more potent than the corresponding norfloxacin and pipemidic acid dimers. For the linkers, p-xylenyl, m-xylenyl and 2,6-lutidinyl were more favorable than 1,4-trans-2-butenyl and 1,1′-biphenyl-4,4′-dimethylene. In particular, asymmetric dimers 4a,b and symmetric dimers 4c with MIC of <0.03-0.125 µg/mL against SA 1199, SA 1199-3, SA 1199B and MRSA strains were ≥4 folds more active than the three references, and all of them (MIC: 4, 2 and 8 µg/mL, respectively) also exhibited promising activities against GISA. Further studies indicated that this kind of dimers also endowed with great potency against drug-sensitive and drug-resistant Streptococcus pneumonia (S. pneumonia), and unlike ciprofloxacin (which targets topoisomerase IV), several lines of evidence revealed that the dimers act through DNA gyrase in S. pneumoniae and S. aureus, and the switch in target preference may be responsible for their greater lethality [27-36]. Moreover, this kind of dimers were also no inferior to the parent against
Gram-positive S. pyogenes, Mycobacterium tuberculosis (MTB) H37Rv as well as Gram-negative E. coli, vancomycin-resistant Enterococcus faecium (VRE) and P. aeruginosa [27-31], indicating their potential for the development of novel antibacterials.
Azéma et al. have evaluated C-7/C-7-linked ciprofloxacin dimers 5,6 and C-6/C-6-linked levofloxacin dimers 7 as potential antitumor, antibacterial and antimycobacterial agents [37]. The results revealed that the main activity of the dimers was specifically oriented against the inhibition of S. aureus growth or tumor cells growth, but no significant activity on MTB. Ciprofloxacin dimers 5e and 6e exhibited IC50 values from 3 to 8 µM and from 0.1 to 9 µM against all cancer cell lines that were 15-40 and 32-890 folds lower than that of the parent ciprofloxacin (IC50: 89-476 µM), whereas the levofloxacin dimer 7f exhibited the most potent activity with IC50 values ranging from 0.2 to 0.7 µM which was 100-1,240 folds lower than that of levofloxacin (IC50: 67-622 µM). Further analysis suggested that these dimers were able to overcome the natural resistance of certain cancer cell types to apoptosis and thus they might exert their antitumor activities through the activation of apoptotic or non-apoptotic cell death processes. The antibacterial activity of the levofloxacin dimers 7 was generally more active than ciprofloxacin dimers 5,6 against Gram-negative pathogens (P. aeruginosa and E. coli), while the latter was more potent than the former against S. aureus. Among them, ciprofloxacin dimers 5b-e and 6b-d which were highly active against drug-sensitive S. aureus (MIC: ≤0.97 µM), also demonstrated promising activities against two MRSA and two
multidrug-resistant clinical isolates with MIC of 0.0081-125 µM. In particular, dimer 6d with MIC of 0.06 µM against two MRSA strains, 1.9 and 15.6 µM against two multidrug-resistant S. aureus clinical isolates, has the potential to treat MRSA and multidrug-resistant S. aureus infections. The polyethylene glycol thiourea linked norfloxacin and ciprofloxacin dimers 8a,b (MIC: 3.9->125.4 µM) were far less potent than the parents norfloxacin and ciprofloxacin (MIC: 1.3->6.2 µM) against the majority of the tested pathogens, indicating the linkers between the two quinolone cores are crucial for the activity [38].
Fluoroquinolone-1,2,4-triazole-5(4H)-thione hybrids demonstrated excellent antibacterial activities [39-41], so incorporation of 1,2,4-triazole-5(4H)-thione motif into fluoroquinolone dimers may provide more effective antibacterial candidates. Four 1,2,4-triazole-5(4H)-thione tethered nalidixic acid-norfloxacin/ciprofloxacin 9 showed considerable activities against E. coli, Y. pseudotuberculosis, P. aeruginosa, S. aureus, E. faecalis, B. cereus and M. smegmatis with MIC of <1-78 µg/mL [42]. The SAR indicated that nalidixic acid-ciprofloxacin conjugates 9c,d (MIC: <1-9.7 µg/mL) were more potent than the corresponding nalidixic acid-norfloxacin conjugates 9a,b, and were far more active than the reference ampicillin (MIC: 10->128 µg/mL) against all tested strains.
The s-triazine tethered ciprofloxacin dimer 10a and its derivative 10b possessed broad-spectrum antibacterial activities, and their activities (MIC: 0.25-2 µg/mL) against S. aureus, Enterococcus, E. coli, Proteus, Shigella, Klebsiella, Pseudomonas and K. pneumonia were no inferior to the parent ciprofloxacin (MIC: <0.125-1 µg/mL) generally [43]. However, the dimer 10c was inactive against the tested both Gram-positive and Gram-negative pathogens [44].
Compared with free form, metal-chelated derivatives may have profound effects on their biological activities, and some metal chelating agents which are exemplified by ferroquine are potential drugs or have already used in clinical practice [45,46]. The recent studies suggested that the incorporation of a metal ion into the quinolone is an essential step in the mechanism of action of these drugs [47-49], and metal ion metabolism in vivo has been the target of antibacterial strategies for many years and can be deemed as the starting point for the growing discussion of nutrient metal homeostasis at the pathogen-host interface [50-52]. The 4-oxo-3-carboxylic acid moiety is indispensible for hydrogen bonding interactions with DNA bases in the single-stranded regions of dublex DNA created by the action of the enzyme and bacterial membrane transport, and Mg2+ modulated DNA-affinity of the quinolones through chelated with 4-oxo-3-carboxylic acid moiety plays a pivotal role in poisoning the cleavable gyrase-DNA complex and, consequently, in eliciting antibacterial activity by this family of drugs [53,54].
Since a host of low-molecular-weight Cu2+ complexes have been proven beneficial against several diseases, incoproation of Cu2+ between two quinolones is among one of the most widely complexes in this field [55]. Interaction of Cu2+ with deprotonated complexes showed excellent activities against Gram-positive pathogens including drug-resistant bacteria MRSA [57]. Almost all of complexes were comparable to or more active than the three references gatifloxacin, sparfloxacin and gemifloxacin.
A set of novel fluoroquinolone dimers including ofloxacin, pefloxacin, gatifloxacin, norfloxacin, levofloxacin and sparfloxacin-Pt2+ complexes was assessed for their antibacterial activities by Patel et al. [58]. A significant part of the complexes was more potent than the parents, and the fluoroquinolone moieties impacted the activity in the order of sparfloxacin > pefloxacin ≈ levofloxacin > ofloxacin > norfloxacin > gatifloxacin. The most active bis-sparfloxacin-Pt2+ complex 13 with MIC of 0.2-0.5 µM was 2-25.5 times more potent than the six references against the tested both Gram-positive and Gram-negative bacteria, could act as a lead for further exploitations.
The bis-fluoroquinolone-metal complexes ofloxacin-Ti4+/Y3+/Ce4+ [59], moxifloxaxin-V4+/Zr4+/U6+ [60], levofloxacin-Zn2+/Ni2+ [61], norfloxacin-Zn2+/Ni2+Ag+/Au3+ [62,63], ciprofloxacin/gatifloxacin/norfloxacin/levofloxacin-V4+ [64], sparfloxacin-U4+/La3+/Cr3+/Fe3+ [65] as well as bis-quinoline-metal complexes [66,67] also demonstrated potential antibacterial potency against various bacteria including drug-resistant pathogens, and some of them were as active as the parent drugs, but the majority of them were less potent than the parents.
3. Anti-Cancer activity
Cancer, the uncontrolled growth of cells which can affect almost all part of the body and has many anatomic and molecular subtypes, is an ancient disease has been a scourge of humanity for thousands of years [68,69]. Cancer is the second leading cause of death globally, only behind cardiovascular disease, and lung, prostate, colorectal, stomach and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervix and stomach cancer are the most common among women [70,71]. The WHO has estimated that approximately 14 million of new cases and 8.8 million cancer-related deaths occurred every year, and the financial costs of cancer were estimated at $1.16 trillion dollars annually as of 2010 [71,72]. The global pandemic of drug sensitive cancers and the increasing threat from drug-resistant cancers have driven the drug discovery of more effective anti-cancer candidates [73]. In spite of several anti-cancer candidates with diverse novel structures are under
evaluated for their in vitro anti-tumour activities against a panel of cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC-7721) by Li et al. [78]. The premiliary results indicated that all dimers showed moderate to excellent cytotoxic activities (IC50: 0.011-3.56 µM) against the different cancer cells with potencies in the single-digit µM range and most of them with high selectivity towards the H460 and MKN-45 cell lines. The SAR revealed that the introduction of different functional group at R1 position only slightly altered cytotoxicity, indicating that the R1 group contributed little to potency. Substituents at R3 position have great influence on the anti-tumour activities, and no substitution and mono-electron-withdrawing groups were preferred, while double-electron-withdrawing groups and electron-withdrawing groups were detrimental to the activity. It is worth mentioning that the position of the R3 group was also closely related to the activity, and substituents at meta-position were more favorable than para-position. Dimers 15 were more potent than the corresponding analogs 14, suggesting installation of -F at R2 position could enhance the activity. Among them, dimers 14d, 14e, 14m, 14n, 15a, and 15i (IC50: 0.011-0.92 µM) exhibited more potent activity against all five human cancer cell lines than the reference foretinib (IC50: 0.031-1.04 µM). The six dimers also displayed excellent c-Met enzymatic potency with IC50 values in a range of 1.32-3.45 nM, suggesting that the inhibition of c-Met may be a mechanism for their anti-tumor effect. In particular, dimer 14e with IC50 of 0.011-0.15 µM was 2.9-10.9 times more potent than foretinib against all tested cancer cell lines, was also comparable to foretinib in the inhibition of c-Met kinase (IC50: 1.32 and 1.16 nM), indicating that this dimer deserves further investigation. Further studies indicated that quinoline motif can be replaced by 2-quinolone (16) [79], but replaced by 2-naphthyridinone was disfavored [80]. 2-Quinolone-quinoline derivative 16a which was found to be most active against all tested five human cancer cell lines (IC50: 0.031-0.52 µM), was 6.1, 2.4, and 2.1 times more active than foretinib against H460, HT-29, and U87MG cell lines. Compared with its high potency against c-Met (IC50: 1.21 nM), compound 16a also exhibited high inhibitory effects against Flt-3 (IC50: 2.15 nM), but weak potency on c-Kit, VEGFR-2, PDGFR-b, and EGFR (IC50: 362.8->100,000 nM) [79]. These data suggested that compound 16a mainly acts on c-Met and Flt-3, and it can be act as a lead for further optimization.
42 nM) at para-position or -CF3 (17e, CC50: 123 nM) at orth-position reduced the cytotoxicity. The cytotoxic activity of dimers 17b,c was further investigated on a panel of human cancer cell lines and on two non-cancerous cell lines, and both of them showed promsing cytotoxicity against the majority of the cell lines with CC50 of 0.8-8.0 nM. Interestingly, dimer 17c was more potent than compound 17b against all tested cell lines. Mechanistic studies revealed that these two dimers did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect, but their cytotoxic effect is potentiated by the pro-apoptotic effects of tumor necrosis factor related apoptosis inducing ligand [81]. Overall, these dimers could represent new promising anti-cancer candidates with specific action mechanisms, targeting accessible thiols from specific proteins and inducing potent anti-cancer effects [82].
The five quinoline dimers 18a-e tethered via pyrimidine showed promising disruptor of telomeric silencing 1-like (DOT1L) inhibitory activities, and IC50 values were 1.06-21.67 µM [83]. The SAR for dimers 18a-c indicated that the anti-DOT1L activity was influenced greatly by substituents at R position, and -NH2 (18a, IC50: 1.5 µM) > -OH (18b, IC50: 4.35 µM) >> -OMe (18c, IC50: 21.67 µM), suggesting the hydrogen bond donor was essential for the high activity. Dimer 18d (IC50: 1.08 µM) was more active than compound 18a, suggested that -Me at pyrimidine fragment was detrimental to the activity. Moreover, dimer 18e (IC50: 1.06 µM) which was slightly more active than its regio-isomer 18d was selected for further evaluation of its in vitro anti-leukemia cell proliferation activity in MLL-expressing acute leukemia cell line MV4-11 and the non MLL-rearranged Kasumi-1 cells. In spite of dimer 18e displayed good anti-DOT1L activity, it (IC50: 30.54 and 45.75 µM) only showed weak anti-leukemia cell proliferation activity, which may attribute to its poor cell membrane permeability.
Besides the above quinoline dimers, some other quinoline dimers also endowed with potential anti-cancer activities [84-88]. The GI50 of 4-aminoquinoline dimer 19 was 7.35 and 14.80 µM against DMA-MB-468 and MCF-7, which was superior to the mono-quinoline derivatives (GI50: 8.22-51.57 µM) [84]. Thus, dimer 19 can serve as the prototype molecule for further development of a new class of anti-cancer agents.
have the potential for treatment or prevention of malaria through their unique antiparasitic effect against erythrocytic and hepatic stages of Plasmodium [14]. The quinoline/quinolone dimers with the incensement in steric bulk are expected to penetrate less into the red blood cell that may not allow destabilization of red cell membrane inducing hemolysis, the main cause of toxicity. Moreover, quinoline/quinolone dimers may have dual-action mechanism, and consequently increase the antiplasmodial and antimalarial activities [94]. The 4-aminoquinoline dimer piperaquine (Figure 7) is at least as effective as chloroquine against P. falciparum and P. vivax malaria and is also effective against chloroquine-resistant (CQR) P. falciparum [95]. Piperaquine has been used extensively in China and Indochina as prophylaxis and treatment, so quinoline/quinolone dimers are very attractive protypes to develop novel antimalarials.
The SAR revealed that the 4-amino-7-chloroquinoline fragment is responsible for inhibition of β-hematin formation and accumulation of 4-aminoquinoline derivatives at the target site, so 4-amino-7-chloroquinoline motif plays a pivotal role in exertion of antiplasmodial and antimalarial activities [96]. Replacement of 7-chloro by either electron-donating groups such as -NH2, -OCH3, or electron-withdrawing groups like -NO2, results in significant loss of activity [97,98]. Thus, 4-amino-7-chloroquinoline dimers with different linkers have caused great interests in recent years.
Several alkanediamines (22) and heteroalkanediamines (23) tethered 4-amino-7-chloroquinoline dimers were screened for their activities against chloroquine-sensitive (CQS) D6 and CQR W2 P. falciparum in vitro and against P. berghei in vivo by Vennerstrom et al. [99-104]. All dimers 22 (IC50: 1.0-83 nM) and 23a-j (IC50: 1.2-89 nM) exhibited potential in vitro antiplasmodial activities against CQS D6 and CQR W2 P. falciparum, and were more active than chloroquine (IC50: 100 nM) against CQR W2 P. falciparum. The SAR revealed that dimers with alkyl ether and piperazine linkers were substantially more effective than the corresponding alkylamine tethered analogs against P. berghei in vivo generally. However, compared to alkylamine-bridged dimers, none of these heteroalkane-bridged dimers had sufficient antimalarial activity to warrant further investigation. The most potent in vitro dimer 22m (Ro 48-6910, IC50: 1.0 and 1.4 nM, respectively) also demonstrated excellent in vivo antimalarial activity-80% and 100% cure rates were achieved at doses of 160 and 320 mg/kg, respectively [99]. However, some cross-resistance between Ro 48-6910 and chloroquine in vitro was observed, and Ro 48-6910 also showed phototoxicity in the pre-clinical evaluations.
The bulky quinoline dimers suggested to be extruded with difficulty by a proteinaceous transporter, so the dimers may be used to overcome chloroquine efflux.
Compared with chloroquine (IC50: 280 and 154 nM, repsectively), quinoline dimers 24a (IC50: 98 and 89 nM, repsectively) and 24b (IC50: 58 and 10 nM, repsectively) was 1.73-15.4 folds more active against CQR W2 and K1 P. falciparum, so both of them have the potential for the tratement of drug-resistant malaria [105]. A series of quinoline dimers with linear or cyclic amino linkers were determined for their in vitro antiplasmodial activities and cytotoxicity toward mammalian cells [106]. The preliminary results indicated that increment of rigidity by cyclization reduced toxicity but could not increase in vitro antiplasmodial activity in comparison with their linear counterparts. The most active quinoline dimer 25a with IC50 values of 64.6-170.1 nM against CQR W2, FcB1R, D6 and F32 P. falciparum, was comparable to chloroquine (IC50: 19-175 nM). Moreover, dimer 25a was no cytotoxicity towards MRC-5 cells and mouse peritoneal macrophages. Dimer 25b, the ferrocene analog of dimer 25a, also showed potential activity against CQS HB3 and CQR Dd2 P. falciparum with IC50 of 110 and 62 nM [107]. It was more efficient on the Dd2 strain than chloroquine (IC50: 94 nM), but was less active on the CQS HB3 P. falciparum. The cyclen linked 7-chloroquinoline dimer 25c (IC50: 4.1, 5.8 and 2.5 nM) without cytotoxicity in VERO cells was more potent than the references chloroquine (IC50: 8.2, 283.5 and 90.0 nM) and mefloquine (IC50: 19.9, 7.2 and 55.8 nM) against CQS D6, CQR W2 and mefloquine-resistant (MQR) TM91C235 P. falciparum, suggesting its potential in treatment of both drug-sensitive and -resistant malaria [108]. In P. berghei-infected mice model, the in vivo antimalarial activity of dimer 25c was comparable to that of chloroquine (50% effective dose, ≤1.1 mg/kg; 90% effective dose, 5.6 mg/kg); no apparent toxicity has been observed up to the highest dose tested (30 mg/kg). The dimer 25c inhibited in vitro hemozoin (β-hematin) formation with an IC50 of 1.1 µM, which was 8.6 folds more potent than chloroquine (IC50: 9.5 µM). All above facts make dimer 25c as a promising antimalarial candidate, and needs to be further evaluated.
cytotoxicity against CHO cells [112]. All 7-chloroquinoline dimers 29 were highly active against D10 and Dd2 P. falciparum with IC50 ranging from 35.49 to 128.59 nM, and were more active than their 5-methylquinoline analogs (IC50: 80.22-1914.01 nM). Introduction of -Me at R1 position was favorable to the activity, and the methyl dimer 29d (IC50: 37.38 and 71.13 nM, respectively) was more active than chloroquine (IC50: 48.35 and 242.30 nM, respectively) against D10 and Dd2 P. falciparum. Moreover, the CC50 of dimer 29d against CHO cells was 7.8 µM, and the selectivity index (SI) was 211. Further investigation revealed that this kind of dimers also displayed excellent anti-cancer activities, and the most active 29a was a more effective antiproliferative inhibitor than etoposide against all three TK10, UACC62 and MCF7 cancer cell lines.
The SAR indicated that the 7-chloroquinoline dimers 30 (IC50: 24-1,430 nM) containing alkylamine linkers were more potent than the corresponding dimers 31 (IC50: 355-2,090 nM) with conformationally rigid piperazine linker against both CQS 3D7 and CQR K1 P. falciparum [113]. The length of the carbon chain linker plays a key role on the antiplasmodial activity against CQR K1 P. falciparum, and short linkers such as two carbons chain were appropriate for the activity, while presence of an isobutyl group in the linker potentiates the activity. The dimer 30d was found to be most active against both CQS 3D7 and CQR K1 P. falciparum with IC50 of 24 and 26 nM, respectively, which was 10 folds more potent than chloroquine (IC50: 255 nM) against CQR K1 P. falciparum. Moreover, dimer 30d showed good SI of 1,011.71, could act as a lead for further optimization.
The 7-chloroquinoline dimers 32 bearing 1,2,3-triazole and β-lactam fragments only displayed weak in vitro antiplasmodial activities with IC50 in µM level, indicating the secondary amine at C-4 position of quinoline motif is essential for the high activity [114].
The 7-chloroquinoline-acridine derivatives showed weak to moderate in vitro antiplasmodial activities against NF54 P. falciparum with MIC of 0.25-1 µg/mL for the development of ring stage parasite into the schizont stage [115]. The SAR indicated that the linkers between quinoline and acridine influenced the activity greatly, and para-/meta-phenylenediamines were more favorable than
ethylenediamine and propylenediamine. Derivative 33a (Figure 8, MIC: 0.25 µg/mL) tethered through meta-phenylenediamine was more active than the para-phenylenediamine analog 33b (MIC: 0.5 µg/mL), but was less active than chloroquine (MIC: 0.125 µg/mL). In vivo in swiss mice infected with CQR N-67 strain of P. yoelii, compound 33a displayed the complete clearance of parasitemia on day 4 at the dose of 50 mg/kg×4 days by ip route, but none of mice survived beyond day 28.
The 7-chloroquinoline-quinoline derivatives 34a,b (IC50: 20.1 and 74.1 nM, respectively) showed great potency against CQR FcB1 P. falciparum, and were more potent than chloroquine (IC50: 126.0 nM) [116]. Compound 34a (CC50: 16.4 µM) also displayed low cytotoxicity against MRC-5 cells, and SI was 816.
The in vivo study in P. berghei N/13 (2×107 parasitized erythrocytes) infected MF1 mice model indicated that dimer 35a was inactive, while compound 35b (ID50: 5.9 mg/kg; 14.9 mmol/kg) was comparable to Ro 48-6910 (ID50: 3.0 mg/kg; 8.3 mmol/kg) [117]. WR319691 and WR319775, which are mefloquine dimers, exhibited reasonable P. falciparum potency in vitro (IC90: 22-80 ng/mL against mefloquine-resistant strain D6 and MDR strain C235 resistant to mefloquine, chloroquine, and pyrimethamine) and reduced permeability across MDCK cell monolayers (0.14×10-6 and 0.3×10-6 cm/s, respectively) [118,119]. Maximum bound and unbound brain levels of WR319691 (Single-dose, i.v. dose of 5 mg/kg in mice) were 97 and 0.05 ng/g versus approximately 1,600 and 3.2 ng/g for mefloquine. The half-life of WR319691 in plasma was approximately 13 h versus 23 h for mefloquine [118]. WR621613 and WR621612 (IC90: ≥329 ng/mL against D6 and MDR C235 P. falciparum), the methyl analogs of WR319691 and WR319775, were far less active than WR319691 and WR319775, suggesting introduction of methyl was detrimental to the activity [119].
vitro antiplasmodial and in vivo antimalarial activities by Hrycyna et al. [120]. The amide 36a and carbamate 36b were inhibitors of PfCRTCQR with IC50 of 5.3 and 1.4 µM, and were far more potent than quinine, verapamil and saquinavir (IC50: 48, 30 and 13 µM, respectively). It is worth noting that both of them were not effluxed by PfCRTCQR from the digestive vacuole but instead accumulated to very high levels within this organelle. Both dimers were found to inhibit β-hematin formation in a dose-dependent manner, and the resulting IC50 values (IC50: 3.4 and 2.5 µM, respectively) were comparable to that measured for quinine (IC50: 3.9 µM). The half-life for both of them was >90 h in plasma, indicating their excellent stability profiles. The two dimers 36a,b (IC50: 32.0-514.1 nM) inhibited the proliferation of CQS HB3 (isolated in Honduras and carrying PfCRTCQS), CQR Dd2 (isolated in
Indochina and carrying the Dd2 version of PfCRTCQR), FCB and P31 (both isolated in South East Asia and carrying the K1 version of PfCRTCQR) P. falciparum with IC50 values in the nanomolar range, although neither dimer was more effective than quinine against the CQS strain, both of them possessed enhanced activities against all tested CQR P. falciparum. A preliminary in vivo evaluation of dimers 36a,b was performed in mice infected with a CQS strain of P. berghei, and the activity of compound 36a (ED50: 38.2 mg/kg) was a bit higher than that of quinine (ED50: 48.7 mg/kg), whereas 36b did not appear to exert an antimalarial effect when administered at doses between 10 and 40 mg/kg. Overall, the dimer 36a could act as a starting point for further investigation.
The in vitro antiplasmodial activity of bistacrine derivatives 37 (IC50: 50-6,110 nM) against CQS 3D7 and CQR Dd2 P. falciparum suggested that the length of the linker influenced the activity significantly, and the longer linkers (n≥5) were more favorable than the shorter linkers (n=1-4) [121,122]. Further structure modification yielded the dimers 38, and all of them (IC50: 20-50 nM) were comparable to chloroquine (IC50: 20 nM) against CQS 3D7 P. falciparum [121]. In particular, the most active dimer 38f (IC50: 20 nM) also displayed low cytotoxicity (CC50: 25 µM) against J774.1 cells, and SI was 1,250. The mechanism study indicated that dimer 38f (IC50: 5.2 µM) could target the cysteine protease falcipain-2, which is essential for parasite growth.
The thieno[3,2-c]quinoline dimers (IC50: 210-2,100 nM and 50-4,100 nM against CQS 3D7 and CQR Dd2 P. falciparum, repsectively) were far less potent than chloroquine (IC50: 21 and 210 nM, repsectively) against both against CQS 3D7 and CQR Dd2 P. falciparum, but dimer 39 (Figure 9) displayed promising in vivo activity in P. vinckei infected mice with an ED50 of 30 mg/kg after i.p. administration [123]. The IC50 values of chloroquine dimers 40 were 43-454 and 17-25 nM against CQS
Twelven quinoline dimers 41, 42 and 43 (Figure 9) were evaluated for their in vitro antiplasmodial activities against CQS D10, CQR K1 (resistant to chloroquine but sensitive to mefloquine) and K1mef (resistant to mefloquine) P. falciparum by Cowman et al. [125]. All dimers showed promising activities against all tested with IC50 in a range of 20-980 nM, and the antiplasmodial activity order was 42>43>41. Dimers with four-carbon linkers were more potent than other analogs, and similar results were also observed for dimers 44 [126,127]. Compound 42d with IC50 of 50, 20 and 20 nM against CQS D10, CQR K1 and K1mef P. falciparum was found to be most active. Further evaluation in vivo against the rodent malaria P. yoelii nigeriensis (the most resistant murine strain to chloroquine) proved that dimer 42d (IC50: 5.2 mg/kg) was less potent than chloroquine (IC50: 2.5 mg/kg). Moreover, dimer 42d was severely toxic to the mice at concentrations greater than twice the IC50 dose, and when the compound was administered orally at 25 mg/kg, the mice survived but the inhibition was only 13%.
A series of 8-aminoquinoline dimers tethered via various linkers including amino acids were screened for their in vitro antiplasmodial and in vivo antimalarial activities and cytotoxicity in VERO cells by Jain et al. [94]. All dimers were no toxic towards VERO, and the antiplasmodial activity (IC50: 0.3-4.76 µg/mL) against both CQS D6 and CQR W2 P. falciparum, and was comparable to primaquine (IC50: 2.0 and 2.8 µg/mL, respectively). The most promising dimer 45 (IC50: 0.34 and 0.3 µg/mL, respectively) was found to be 6- and 9-fold more potent than primaquine against CQS D6 and CQR W2 P. falciparum. The in vivo study in P. berghei infected mice indicated that dimer 45 exhibited significant in vivo blood-schizontocidal antimalarial activity with 100% cures at 25 mg/kg and was suppressive (5/6 cures) at 10 mg/kg, while primaquine was inactive even at 100 mg/kg.
The quinoline and quinolone dimers 46 [128] and 47 [129] were inactive, while dequalinium 48 [130] was able to inhibit both processes in vitro with close correlation to a murine malaria model, reducing parasitemia levels, prolonging the survival time post-infection and curing 40% of infected mice using a combination therapy with a loading dose of chloroquine. Dimer 49, the metabolite of piperaquine, was a highly potent reverse CYP3A inhibitor with IC50 of 0.043 µM, which was far more potent than piperaquine (IC50: 0.76 µM) [131]. Thus, it could act as a starting poing for further investigation.
5. Anti-tubercular activity
Tuberculosis (TB) is an infectious disease mainly caused by the bacterium Mycobacterium tuberculosis (MTB), and TB has been the ninth leading cause of death around the world, ranking above HIV/AIDS [132,133]. Drug-resistant TB (DR-TB), especially multi-drug resistant TB (MDR-TB), is a persistent problem for the treatment of the global TB epidemic [134]. Approximiately 10.4 million incident cases and 1.67 million deaths occurred in the year 2016, and around 600,000 incident cases was rifampicin-resistant TB, of which 490,000 cases were MDR-TB [132]. Therefore, it is imperative to develop novel agents to treat both drug-susceptible and -resistant TB.
Quinoline and quinolone derivatives were reported to possess promising anti-TB activities, and some of them such as bedaquiline and ciprofloxacin have received approval for the treatment of MDR-TB infected patients. The hydrophobicity cell envelop of mycobacteria is a natural barrier that prevents many agents from penetrating into the bacteria, so the lipophilicity of drugs plays a pivotal role in the penetration into mycobacterial cells [10]. Simply increasing the lipophilic character may also increase the anti-TB activity, while quinoline and quinolone dimers were more lipophilic than the corresponding mono-derivatives, so quinoline and quinolone dimers were reasonable choice to develop new anti-TB agents.
All quinoline dimers 50 (Figure 10) showed considerable activities with MIC in a range of 1.1 to 43.4 µM against MTB clinical isolate (resistant to isoniazid, rifampicin, ethambutol and ciprofloxacin) [135]. The SAR revealed that compared with the unsubstituted dimers 50a-k, dimers 50l-q with -Cl at R2 position displayed higher activities. Introduction of electron-withdrawing halogen atoms -Cl and -Br at the phenyl ring (Ar) could enhance the activity, while electron-donating -Me and -OMe were disfavored. Halogen atoms -Cl and -Br at the meta-position of phenyl ring (Ar) were more favorable than para-position. Dimers 50o,q were found to be the most active compounds with MIC of 1.1 and 2.2 µM against MTB, and were 2.1-46.4 folds against MTB H37Rv and two MDR-TB isolates by Kalia et al. [136], and all derivatives (MIC: 0.39-3.12 µM) except 51c-e (MIC: >50 µM) with allyl at R1 position were active against the tested strains. The SAR revealed that -Me at R1 position was most favorable, and introduction of -Br on the meta-position of the phenyl ring at R2 position reduced the activity. The most active 51a,g with MIC of 0.39 and 3.12 µM against MTB H37Rv and two MDR-TB isolates, were also no cytotoxicity (CC50: >100 µM) towards VERO cells and mouse bone marrow-derived macrophages. Both of the two derivatives were further investigated in mouse bone marrow macrophage model of TB, and compared with 51a,g demonstrated 90% and 91% reduction in the intracellular colony forming units (CFUs) of MTB which were comparable to the first-line anti-TB agents isoniazid and rifampicin (produced 98% reduction in the CFUs), and similar results were obtained with human bone marrow macrophage model of TB. In in vivo MTB H37Rv infected outbred Swiss mice model, dimer 51a could reduce the bacterial load in the lungs by 118-fold at 50 mg/kg dose and 808-fold at 100 mg/kg dose and was no inferior to isoniazid (257.08-fold at 25 mg/kg) and ethambutol (26.94-fold at 25 mg/kg). All the mice survived up to day 29 in the group fed with 50 mg/kg dose, whereas one mouse died on day 9 in the group given the compound at 100 mg/kg.
The hydrozone linked quinoline dimers 52 (MIC: 2.2-9.6 µM) showed moderate anti-TB activities and were less active than isoniazid and rifampicin (MIC: 0.36 and 0.037 µM, respectively) [137]. Moreover, dimers 52 were highly cytotoxic in VERO cells, and SI was around 1. The majority of monocarbonyl curcumin tethered 2-chloroquinoline dimers 53 were inactive against MTB H37Rv with MIC90>30 µg/mL [138]. The most active dimer 53a with MIC90 of 7.8 and 9.4 µg/mL against MTB H37Rv and M. bovis BCG was far less potent than rifampicin (MIC: 0.02 and 0.0173 µM, respectively). The fluoroquinolone dimers were also screened for their anti-TB activities, but they only exhibited weak to moderate activities [139,140].
donovani, and all of them showed encouraging effency with IC50 values of 2.0-13.5 µg/mL against promastigotes and 2.1-10 µg/mL against intracellular amastigotes [143]. The SAR indicated that introduction of -Me at R1 position was detrimental to the activity, while installation of -Cl at R2 position and prolongation of the carbon chain (n) could enhance the activity. In particular, three dimers 56a, 56b and 56f (IC50: 2.0-2.8 µg/mL) were as potent as pentamidine (IC50: 2.1 and 2.8 µg/mL, respectively), but were less active than amphotericitin B (IC50: 0.16 and 0.1 µg/mL, respectively) against promastigotes and intracellular amastigotes. The three dimers also
Seven quinoline derivatives including dimer 58 were evaluated in vitro and in vivo against the nematodes Caenorhabditis elegans, Heligmosomoides polygyrus and the protozoa Trichomonas vaginalis [145]. The in vitro activity of dimer 58 against Caenorhabditis elegans, Heligmosomoides polygyrus and Trichomonas vaginalis was comparable to or slightly less active than the references. The activity against acetylcholinesterase (AChE) of compound 58 was also a little bit less active (67.7% vs. 82.3) than albendazole. Dimer 58 showed some in vivo nematocidal activity against Trichinella spiralis with 31.2% reduction at 200 mg/kg, but was less active than mebendazole (84.2% reduction at 25 mg/kg).
Some quinoline dimers have shown some other biological activities such as promising filarial response and sterilization effect on female Acanthocheilonema viteae in rodents, and dimer 59a was 47% adulticidal, while dimer 59b was 85% microfilaricidal [146,147]. Some quinoline or quinolone dimers also exhibited potential as antischistosomal [148], anti-botulinum neurotoxins [149,150], anti-nociceptive and anti-inflammatory [151], antagonists [152], anti-Alzheimer’s disease [153-155], and anti-fungal [156-158] agents, warrant further investigations.
7. Conclusion
Quinoline and quinolone dimers exhibit various biological and pharmacological properties such as antibacterial, anticancer, antimalarial and antitubercular activities, and some currently used drugs bearing quinoline and quinolone dimers. Therefore, modification of quinoline and quinolone dimers may provide new agents for clinical deployment in the control and eradication of various diseases.
Various quinoline and quinolone dimers were screened for their in vitro and in vivo biological activities by medicinal chemists, and some of them exhibited promising potency. The enriched SAR may pave the way to further rational development of quinoline and quinolone dimers with broader spectrum, more effective, lower toxicity as well as multiple mechanisms of action.
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