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Original article
12 (
7
); 932-945
doi:
10.1016/j.arabjc.2018.10.003

Synthesis, anti-tuberculosis activity and QSAR study of 2,4-diarylquinolines and analogous polycyclic derivatives

, , , , , , ,
a Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Orgánica, C1113AAD Junín 956, Ciudad Autónoma de Buenos Aires, Argentina
b CONICET, Centro de Investigaciones en Bionanociencias, Polo Científico Tecnológico, C1425FQB Godoy Cruz 2390, Ciudad Autónoma de Buenos Aires, Argentina

⁎Corresponding authors at: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Orgánica, Junín 956 C1113AAD, Ciudad Autónoma de Buenos Aires, Argentina. jjcasal@ffyb.uba.ar (Juan J. Casal), elizabet@ffyb.uba.ar (Silvia E. Asís)

Received: , Accepted: ,
© The Author(s) 2018
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Abstract

The multicomponent syntheses of 2,4-di-aryl-quinolines and analogous polycyclic derivatives as anti-tuberculosis agents were described. They were prepared via Beyer and Friedländer methods under microwave irradiation in short reaction times and good yields. Several homogeneous and heterogeneous acid catalysts were compared for preparing 2,4-di-arylquinolines and among them trifluoroacetic acid (TFA) reached the higher yields. Two derivatives exhibited activity against Mycobacterium tuberculosis H37Rv (Mtb), underwent additional testing and were considered lead compounds. The synthesis of a series of polycyclic analogous led to six new active compounds and a Quantitative Structure Activity Relationship study (QSAR) study was established.

Keywords

Substituted quinolines
DARQ
Microwave-assisted synthesis
Catalysis
Mycobacterium tuberculosis
QSAR
1

1 Introduction

Tuberculosis (TB) is caused by bacteria (Mycobacterium tuberculosis) that most often affect the lungs. In 2016, an estimated 1 million children became ill with TB and 250,000 children died of TB (including children with HIV associated TB). Multidrug-resistant TB (MDR-TB) remains a public health crisis and a health security threat. WHO estimates that there were 600,000 new cases with resistance to rifampicin, the most effective first-line drug, of which 490,000 had MDR-TB. Ending the TB epidemic by 2030 is among the health targets of the newly adopted Sustainable Development Goals. By June 2017, 89 countries had introduced bedaquiline and 54 countries had introduced delamanid (a dihydro-nitroimidazooxazole derivative), in an effort to improve the effectiveness of MDR-TB treatment regimens (Tuberculosis Fact sheet, WHO, 2018).

Bedaquiline, previously known as TMC207 (Fig. 1), was developed by Johnson & Johnson pharmaceutical company. This diarylquinoline (DARQ) acts by a novel mechanism by targeting proton pump of adenosine triphosphate (ATP) synthesis, leading to inadequate synthesis of ATP (Andries et al., 2005; Rustomjee et al., 2008). A quinoline moiety is its essential pharmacophoric feature and the bedaquiline performance encouraged several authors for the design and synthesis of new drugs (Tanwar et al., 2016). The quinoline alkaloids 4-methoxy-2-phenylquinoline, graveolinine and kokusagine isolated from Lunasia amara, showed significant activity towards M. tuberculosis H37Rv in vitro (Metallidis et al., 2007). More recently, new 4-substituted quinoline derivatives of the antimalarial drug mefloquine exhibited anti-tuberculosis properties (Eswaran et al., 2010). Furthermore 2-substituted quinolines isolated from plants or prepared by synthesis, have exhibited activity against leishmaniasis (Fournet et al., 1996; Gopinath et al., 2014), Chagas disease (Muscia et al., 2011) and M. tuberculosis (Jain et al., 2003; Patel et al. 2014, 2015). The quinoline ring was shown to confer anti-TB activity and confirms that quinoline-based scaffolds are promising leads for new TB drug developments (Casal and Asís, 2017) as depicted in Fig. 2 for our previously synthesized quinolines A-C (Muscia et al., 2014). We have also reported the microwave-assisted Döbner synthesis of 2-phenylquinoline-4-carboxylic acids and their activities against malaria, trypanosomiasis and leishmaniasis (Muscia et al., 2008). The parent compound 2-phenyl-4-quinolincarboxylic acid 4 (Atophan) and its analogous 5, 6, 7 and 8, were further evaluated for growth inhibitory activity towards M. tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA) and showed no activity (Scheme 1, A). Since 2-styrylquinoline-4-carboxylic acids had not been sufficiently explored as anti-TB agents and thus the effect of a vinyl group, we have synthesized a series of ten derivatives. Only the compounds featuring the 3,5-di-OCH3-phenyl, 3,4-methylendioxyphenyl and 1-naphthyl moieties attached at the C2 of vinyl group showed weak activity against M. tuberculosis under aerobic conditions (Muscia et al., 2017). Thus the analogous 2-aryl-4-quinolin-carboxylic acids 9–11 and 14 were prepared (Scheme 1, A and B). Although these four derivatives had been already reported, their NMR spectra were not described. Moreover, compound 9 with a 1-naphthyl ring attached at C2 was cited for the treatment of TB (Tsatsas et al., 1955) but these data are not available. Later, the family of DARQ 16–23 was prepared via the Beyer method, another multicomponent reaction (MCR), with the aim to analyze the effect of introducing a second aryl moiety at C4 of the quinoline ring (Scheme 2).

Chemical structure of bedaquiline.
Fig. 1
Chemical structure of bedaquiline.
Lead fused quinolines A-C.
Fig. 2
Lead fused quinolines A-C.
Synthesis of 2-aryl-4-quinolincarboxylic acids 4–11 and 14 via Döbner and Pfitzinger reactions.
Scheme 1
Synthesis of 2-aryl-4-quinolincarboxylic acids 4–11 and 14 via Döbner and Pfitzinger reactions.
Synthesis of 2,4-DARQ 16–23 via Beyer method.
Scheme 2
Synthesis of 2,4-DARQ 16–23 via Beyer method.

Finally, the DARQ series was extended to the polycyclic and fused quinolines 26–45 analogous to our lead compounds (Schemes 3 and 4). A computational analysis of the different molecular descriptors for each product was performed in order to establish a Quantitative Structure Activity Relationship (QSAR) study.

Scheme 3
Synthesis of quinoline derivatives 44 and 45 via Beyer method.
Scheme 4
Synthesis of quinoline derivatives 44 and 45 via Beyer method.

2

2 Results and discussion

2.1

2.1 Chemistry

The microwave-assisted Döbner reaction from substituted anilines (1), arylaldehydes (2) and pyruvic acid (3) was employed to prepare 2-aryl-4-quinoline carboxylic acids 9–11, (Scheme 1, A) (Muscia et al., 2008). Although the yields of this MCR are poor, it is worthy to use in order to achieve in short reaction times a wide variety of substituted quinolines from easily affordable starting materials. Furthermore, this work showed that microwave irradiation (MW) improved all yields compared to two-hour thermal heating. To complete this first series, the Pfitzinger reaction (Pfitzinger, 1886) from isatine (12) and 3-acetyl-phenanthrene (13) was used to afford compound 14 (Scheme 1, B).

In order to determine the effect on the anti-TB activity of a second aryl moiety attached at position 4 of the quinoline, the pyruvic acid of Döbner synthesis was replaced for a variety of methyl aryl ketones (15) maintaining the same neat reaction conditions (Scheme 2). Therefore, 2,4-diarylquinolines 16–23 were obtained via the microwave assisted one-pot Beyer method (Beyer, 1886), as a modification of the Döbner-Miller reaction. Owing to the low yields, the addition of homogeneous catalysts, trifluoroacetic acid (TFA) and Eatońs reagent (Eaton et al., 1973), and heterogeneous catalysts (sulfamic acid (H2NSO3H) and Amberlyst® 15) was evaluated. The reaction times and yields for compounds 16–23 are shown in Table 1. TFA catalysis proved to be more effective as long as the yields were between 35 and 89% and the reactions times were within 1.5–9 min. Whereas for compounds 21 and 22, Eatońs reagent and no catalyst, respectively, exhibited the best performances.

Table 1 Preparation of compounds 16–23 with acid catalysts.
Compd No Catalyst TFA Eatońs H2NSO3H Amberlyst® 15
Time
(min)		 Yield
(%)		 Time
(min)		 Yield
(%)		 Time
(min)		 Yield
(%)		 Time
(min)		 Rto
(%)		 Time
(min)		 Yield
(%)
16 6 63 9 89 10 43 6 19 5 19
17 20 30 3 56 3 13 4 50 nr –
18 6 <10 2.5 44 1 26 2 24 5 <10
19 3 49 1.5 76 14 35 3 49 3 13
20 4 18 5 52 2 24 4 27 2 <10
21 10 13 5 12 6 37 6 32 1 11
22 6.5 38 2 <10 2 30 2 <10 2 <10
23 6 <10 4 35 3 20 2 <10 2 <10

A variety of synthetic methods have been developed to obtain 2,4-disubstituted quinolines. In this regard, 2,4-diarylquinolines were prepared by reactions of o-isocyano-β-methoxystyrenes with nucleophiles, from 2-iodoanilines and alkynyl aryl ketones, Silver-catalyzed cascade reaction of o-aminoaryl compounds with alkynes, among others. The synthesis of compounds 16 (Tanwar et al., 2016; Kobayashi et al., 2004; Prasad Korivi and Cheng, 2006; Tang et al., 2011; Li et al., 2011; Zhang et al., 2013; Xu et al., 2016), 17 (Ahmad et al., 2012), 19 (Kobayashi et al., 2004; Tang et al., 2011; Palimkar et al., 2003; Rehan et al., 2015; Muscia et al., 2006), 21 (Tang et al., 2011; Zhang et al., 2013; Enugala et al., 2008) and 22 (Xu et al., 2016; Rehan et al., 2015) were reported by these or other two-steps methods involving long reaction times and expensive reagents or by MCR with high-priced catalysts. Recently, compounds 16, 19 and 22 were obtained in comparable yields to our work, via MW-assisted Povarov reaction in the presence of p-sulfonic acid calix[4]arene (CX4SO3H) as catalyst (Liberto et al., 2017). The synthesis of compound 18 was found as a progress report from the reaction of 2-vinylaniline and piperonal after 15 h in refluxing toluene and 40% yield, and its melting point and NMR spectra were not given (Walter, 1998). Compounds 20 and 23 have not been previously described. The last one possesses a 4-sulfonamido-5-methylisoxazol-3-yl substituent at C6 position and was prepared from sulfamethoxazole, a recognized antimicrobial agent and thus a pharmacophore moiety for anti-TB activity (Aly, Abadi, 2004).

The above described experimental conditions support that the MW-assisted Beyer method for the synthesis of 2,4-diarylquinolines promoted by TFA is a rapid, neat and versatile reaction that can be extended to a large variety of 2,4-diarylquinolines successfully prepared in short times.

Taking into account the remarkable anti-TB activity results for compounds 14 and 18 (Section 2.2.1) and considering our former lead fused quinolines A-C (Fig. 2), the analogous 26–43 were synthesized employing MW-assisted Friedländer reaction (Scheme 3) (Muscia et al., 2014) and 44–45 through the Beyer method (Scheme 4), both under TFA catalysis.

The tetrahydroacridine derivative 26 was prepared in 2015 using a tandem process that involves in situ aerial oxidation of the corresponding alcohol followed by Friedländer annulation in the presence of KOH at 80 °C for 7 h (Anand et al., 2015). Recently was reported the water mediated green Friedländer synthesis of the polycyclic quinolines 28–32 and 34 under diluted HCl catalysis at room temperature. Although the authors obtained comparable yields to ours, the reactions proceeded in longer reaction times (Gopi and Sarveswari (2017)). Finally the 4-indolylquinoline derivative 44 was cited by Chen et al. in 2015 in a process that involves two steps, the Michael addition of indole to a nitrochalcone followed by a reductive cyclization of the indolylnitrochalcone intermediate.

The spectroscopical analysis of our products agrees with the reported data. All our synthesized quinoline derivatives were obtained in short reaction times under eco-friendly conditions, ease of purification and the ready availability of the starting materials. These advantages are imperative for designing biological active compounds.

2.2

2.2 Biological activity

2.2.1

2.2.1 In vitro activity against M. Tuberculosis

Initially the 2-aryl-4-quinoline carboxylic acids 9–11, 14 and DARQ 16–23 were evaluated for growth inhibitory activity towards M. tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA) and rifampicin was used as reference drug (NIH/NIAID Task Order A01 Contract HHSN272201100012I).

Compounds 14, 18 and 19 exhibited IC50 values of 60.25, 29 and 19 µM, respectively but only compounds 14 (2-phenanthren-3-yl) and 18 2-(3,4-methylenedioxyphenyl) underwent additional testing and are also considered lead compounds. This subset was determined by an algorithm that considered primarily activity and analytical quality of the samples but also considered other aspects such as chemotype series and solubility. This testing includes in vitro evaluation of H37Rv under both anaerobic and aerobic conditions as well as minimal bactericidal concentration (MBC). Single drug resistant strain testing (isoniazid, rifampicin and ofloxacin resistant Mtb strains) and intracellular inhibition of Mtb H37Rv growth using murine macrophage cell line and cytotoxicity in this cell-line were also determined.

The twenty derivatives 26–45 designed as analogous of lead compounds A-C, 14 and 18 (Schemes 3 and 4) were evaluated against Mtb using rifampicin as reference drug (MIC 0.0072 µM) and six of them showed inhibitory activity (Table 2). The additional halogen atom (Cl or F) attached at C2 of the 4-phenyl moiety in compounds 26–29 did not improve the IC50 values of A-C. The chlorine atom at C6 of quinoline ring in compound 38 conferred less activity meanwhile the trifluormethyl group increased the activity comparing to the lead 18 however it was not selected for additional testing. The polycyclic quinolines 35–37 as constrained models of 18 lacked of activity as well as the 2-phenanthryl derivatives 42 and 43 analogous to 14 (Fig. 3).

Table 2 In vitro activity against M. tuberculosis H37Rv of analogous active compounds.
Compd Structure IC50 (µM) IC90 (µM) MIC (µM)
26 81 158 >200
27 65 97 102
28 130 190 200
29 95 >200 >200
38 162 >200 >200
45 21 118 73
SAR of the synthesized quinolines.
Fig. 3
SAR of the synthesized quinolines.

2.2.2

2.2.2 Minimal inhibitory concentration (MIC)

The MIC for each compound was determined by testing ten, two-fold dilutions in concentration ranges. The MIC is reported as the lowest concentration (µM) of drug that visually inhibited growth of the organism. In addition, the percentage of inhibition at the MIC is provided for compound 14 (Table 3). Rifampicin and isoniazid were used as positive controls. Although MIC values of compound 14 were higher than the MIC values for the reference drugs, this compound showed a similar percent inhibition value against the rifampicin resistant strain (RMP-R) and a higher percent inhibition value against the ofloxacin resistant strain (OFX-R). On the other hand, compound 18 had limited activity against M. tuberculosis resistant.

Table 3 Percentage of inhibition at the MIC for compound 14.
Comp MIC
H37Rv
(µM)		 %
Inhiba 		MBC
H37Rv
(µM)		 MIC
INH-Rb
(µM)		 %
Inhib		 MIC
RMP-Rc
(µM)		 %
Inhib		 MIC
OFX-Rd
(µM)		 %
Inhib
14 25.1 60 NAe 12.6 50 25.1 62 6.28 77
Rifampicin
(pos control)		 0.06 57 0.95 0.06 68 NAf NA 0.47 63
Isoniazid
(pos control)		 NA NA NA NA NA 0.15 74 NA NA
a Percent inhibition at the MIC concentration.
b INH-R: Isoniazid Resistance.
c RMP-R: Rifampicin Resistance.
d OFX-R: Ofloxacin Resistance.
e NA: Not Applicable, Colony Counts above the established rejection value of ≥40.
f NA: Not Applicable, Compound not used in assay.

2.2.3

2.2.3 Minimal bactericidal concentration (MBC)

The established rejection value of >40 colonies for the MBC assay was based on the calculated concentration of Mtb in the MIC plates. Results are determined based on Colony Forming Units (CFUs) enumerated from agar plates. Only agar plates with countable colonies have reportable counts. If a compound lacks bactericidal activity, many times the CFUs are too numerous to count (TNTC) and are thus reported as such. This result was the one obtained for compound 14, meanwhile compound 18 proved bactericidal activity so far the MBC value was 100 µM.

2.2.4

2.2.4 Low-oxygen recovery assay (LORA)

Traditional screening of drugs against M. tuberculosis only addresses or targets the organism in an active replicating state. It is well documented that Mtb can reside in a state of non-replicating persistence (NRP) which has not been adequately assessed in the development of new antimicrobials. Results for the LORA assay are reported as the lowest concentration of drug that visually inhibited growth of the organism. This NRP state is considered an antimicrobial tolerance factor, so LORA may identify drugs that could reduce anti-tubercular treatment period. Compound 14 exhibited higher MIC value under anaerobic than under aerobic conditions. Compound 18 had activity against M. tuberculosis under low oxygen conditions and the MIC, IC50 and IC90 values were 136, 7.3 and 30 µM, respectively.

2.2.5

2.2.5 Intracellular drug activity

Intracellular drug activity is reported as log reduction values calculated as reduction in Mtb concentration from zero hour to 7 days post-infection. The three concentrations chosen were based on the MIC data generated in the HTS primary screen. The mid concentration bracketed the reported MIC with the lower concentration ten-fold below the mid and the higher concentration tenfold above the mid. Drug cytotoxicity is reported as cell proliferation, macrophage toxicity (MTT) or percentage of viability. Compound 14 showed a similar tendency as rifampicin, so at higher drug concentrations lower UFC are obtained and the log reduction is higher (Table 4). Concerning cytotoxicity, compound 14 exhibited percentages of viability comparable to rifampicin at low and mid concentrations, so it is not toxic to macrophages. Compound 18 had intracellular activity against M. tuberculosis and was cytotoxic (IC50 = 82 µM).

Table 4 Macrophage toxicity (MTT) and percentage of viability of compound 14.
Comp. Macrophage
log reduction
(low conc)		 Macrophage
log reduction
(mid conc)		 Macrophage log reduction
(high conc)		 MTT
% viability
(low conc)		 MTT
% viability
(mid conc)		 MTT
% viability
(high conc)
14 1.56 1.98 2.54 100 100 80
Rifampicin 0.58 2.00 2.98 90 79 82

2.3

2.3 QSAR study

The analogous compounds 26–29, 38 and 45 have been classified as 'active' and the remaining structures as 'inactive'. All the active molecules have pIC50 values above 4.22 log units. The molecules were built with ChemAxon Marvin Sketch 6.0 and exported to MOL2 format. A total of 1444 1D and 2D different molecular descriptors were calculated using PaDEL-Descriptor v2.7, Table 5 (Todeschini and Consonni, 2009). Descriptors with zero standard deviation in their values were then removed. The principal component analysis (PCA) showed that three principal components (PC) explained 97% of the variance in the chemical structure. The first three PCA vectors were added to the study table containing the binary representation of the activity of the molecules (Tables 6 and 7). Summarizing, PC1 is related to the number of aromatic bonds, PC2 with the effect and position of the substituents and PC3 with the molecular distances between atoms and the tertiary quinoline nitrogen.

Table 5 Calculated molecular descriptors for compounds 26–45.
Compd AMR nHBAcc nHBDon nRing nRotB Ro5 Failures TPSA MW XLogP
26 26.37 1 0 4 1 1 12.89 327.058 6.380
27 29.28 1 0 4 1 1 12.89 341.073 6.949
28 21.62 1 0 4 1 1 12.89 311.087 6.243
29 24.54 1 0 4 1 1 12.89 325.103 6.812
30 23.3 3 0 6 1 1 31.35 405.032 6.098
31 21.14 5 0 4 2 1 73.10 318.100 5.846
32 39.5 2 0 4 1 1 29.96 369.068 6.210
33 23.74 2 0 4 1 0 29.96 325.066 4.959
34 3.89 4 0 6 3 1 56.03 426.136 12.668
35 11.36 6 0 5 3 1 74.49 370.095 7.322
36 16.97 6 0 5 3 1 74.49 404.056 6.363
37 22.87 2 0 4 1 1 29.96 307.076 6.055
38 13.08 3 0 5 2 1 31.35 359.071 7.531
39 18.7 3 0 5 2 1 31.35 393.032 6.572
40 5.615 1 0 6 2 1 12.89 415.112 12.877
41 28.48 2 0 4 1 1 29.96 341.037 5.096
42 17.68 3 0 6 1 1 31.35 371.071 7.057
43 10.77 4 1 6 2 1 47.14 364.121 6.034
44 13.96 3 0 5 2 1 31.35 377.061 6.435
45 13.9 3 0 5 3 1 31.35 393.097 8.549
Table 6 Eigenvectors for the first components.
Principal Component VR2Dta nBondsMb nAtomPc MDEC-23d nssCH2e nwHBaf C2SP2g
PC1 0.1087 0.5011 0.456 0.5194 −0.1219 0.3972 0.2942
PC2 0.9873 −0.0316 0.0092 −0.1446 −0.0257 −0.0413 −0.0246
PC3 −0.1108 0.0458 0.5291 −0.7276 −0.3088 0.0126 0.2825

Major contribution property values to each PC are depicted in bold.

a Normalized Randic-like eigenvector-based index from detour matrix.
b Total number of bonds that have bond order greater than one.
c Number of atoms in the largest pi system.
d Molecular distance edge between all secondary and tertiary nitrogens.
e Count of atom-type E-State: —CH2—.
f Minimum E-States for weak Hydrogen Bond acceptors.
g Doubly bound carbon bound to two other carbons.
Table 7 Principal components for each tested compound.
Compound PC1 PC2 PC3
26 −11.534 −3.415 −1.432
27 −10.755 −3.2 −2.983
28 −11.534 −3.415 −1.432
29 −10.755 −3.2 −2.983
30 4.005 −1.841 −1.331
31 −7.314 −0.285 1.867
32 −9.959 1.55 1.858
33 −9.305 −2.506 0.313
34 24.349 −4.6 −1.443
35 4.53 −2.449 4.007
36 5.31 1.178 3.073
37 −7.459 15.38 −1.526
38 2.649 −2.554 2.386
39 3.433 1.112 1.447
40 22.488 −4.523 −3.086
41 −9.305 −2.506 0.313
42 4.483 2.426 −1.824
43 10.869 14.144 −0.758
44 3.433 1.112 1.447
45 2.368 −2.408 2.087

3

3 Conclusion

We herein describe the multicomponent, eco-friendly synthesis of 31 quinoline derivatives in short reaction times and from easily affordable starting materials and their anti-TB activity. Among the synthesized compounds, fifteen are novel structures and the remaining terms have been reported in the literature although prepared by other experimental conditions and from different expensive starting materials. All products were evaluated in vitro against M. tuberculosis (Mtb) H37Rv. Nine compounds showed inhibitory activity and compounds 14 and 18 underwent additional testing. Compound 18 had limited activity against M. tuberculosis resistant, proved to be bactericidal and had activity against M. tuberculosis under low oxygen conditions, although was cytotoxic. By contrast, compound 14 had a higher percent inhibition value against the ofloxacin resistant strain (OFX-R), lacked of bactericidal activity, was not active under low oxygen conditions and exhibited percentages of viability comparable to rifampicin at low and mid concentrations, so it was not toxic to macrophages. Considering the established minimal structural requirements supported by theoretical calculations, it is worthy to note that the introduction of a sulfonamide moiety at C6 of the quinoline ring in future series could improve the anti-TB activity and diminish the cytotoxicity.

4

4 Experimental section

4.1

4.1 Chemistry

The structures of the synthesized compounds were established through their 1H and 13C NMR, MS and IR spectra. Melting points were determined in a capillary Electrothermal 9100 SERIES-Digital apparatus and are uncorrected. 1H and 13C NMR spectra were recorded at room temperature using a Bruker 300 spectrometer. The operating frequencies for protons and carbons were 300.13 and 75.46 MHz, respectively. When indicated, the spectra were obtained using a Bruker 600 spectrometer. The operating frequencies for protons and carbons were 600 and 151 MHz, respectively. The chemical shifts (δ) were given in ppm. IR spectra were recorded on an FT Perkin Elmer Spectrum One from KBr discs. Mass spectra were measured on MS/DSQ II Thermo Scientific DIP or Agilent MSD, electrospray ionization, positive ion. Elemental analysis (C, H and N) were performed on an Exeter CE 440 and the results were within ±0.4% of the calculated values. Analytical TLCs were performed on DC-Alufolien Kieselgel 60 F254 Merck. Microwave-assisted reactions were carried out in a CEM Discover oven.

4.1.1

4.1.1 2-Arylquinoline-4-carboxylic acids

4.1.1.1
4.1.1.1 General procedure for compounds 9–11

A mixture of the corresponding aniline (0.37 mL, 4.1 mmoles), arylaldehyde (0.58–0.73 g, 3.9 mmoles) and pyruvic acid (0.30 mL, 4.3 mmoles) placed in a 50 mL round-bottomed flask was subjected to MW irradiation at 400 W and 250 °C. After completion of the reaction (TLC), the reaction mixture was allowed to cool and the residual semisolid crystallized. When this did not occur, the reaction mixture was diluted with CH2Cl2 (15 mL) and washed with water, 5% HCl (10 mL) and brine (10 mL). This was then dried (Na2SO4) and concentrated in vacuo to give a solid product (Muscia et al., 2008).

4.1.1.2
4.1.1.2 2-(3,4-methylenedioxyphenyl)quinoline-4-carboxylic acid 9

White solid; yield 45%, mp 215–218 °C, crystallized from EtOH. 1H NMR (DMSO‑d6): δ 6.13 (s, 2H, OCH2O), 7.08 (d, J = 8.1 Hz, 1H, H-Ph), 7.66 (1H, t, Het-H), 7.79–7.85 (2H, m, Ph-H and Het-H), 7.87 (1H, s, Ph-H), 8.11 (1H, d, J = 8.5 Hz, Het-H), 8.39 (1H, s, Het-H), 8.59 (1H, d, J = 8.5 Hz, Het-H). 13C NMR (DMSO‑d6): δ 101.63 (OCH2O), 107.05, 108.68, 118.81, 121.84, 123.29, 125.33, 127.40, 129.64, 130.19, 132.24, 137.63, 148.26, 149.08, 155.21 (Carom), 167.7 (COOH). 101.6, 107.0, 108.6, 118.8, 121.8, 123.2, 125.3, 127.4, 129.6, 130.1, 132.2, 137.6, 148.2, 149.0, 155.2, 167.7. IR (cm−1): υ 3392, 3004, 1715, 1264, 1036, 764, 690. MSD 292 (M+).

Anal. Calcd. for C17H11NO4: C, 69.62; H, 3.78; N, 4.78. Found: C, 69.58; H, 3.72; N, 4.81.

4.1.1.3
4.1.1.3 2-(naphthalen-1-yl)quinoline-4-carboxylic acid 10

Pale yellow solid; yield 25%, mp 170 °C d, Lit. 198 °C (Buu-Hoï, 1943), crystallized from cyclohexane. 1H NMR (DMSO‑d6): δ 7.46–7.47 (2H,m, Ph-H), 7.61 (1H, t, Het-H), 7.66 (1H, t, Ph-H), 7.71 (1H, t, Het-H), 7.83–7.87 (2H, m, Ph-H), 7.93 (1H, d, J = 8.2 Hz, Ph-H), 8.13 (1H, d, J = 7.9 Hz, Ph-H), 8.20 (1H, s, Het-H), 8.25 (1H, d, J = 7.7 Hz , Het-H), 8.51 (1H, d, J = 7.7 Hz, Het-H). 13C NMR (DMSO‑d6): δ 122.9, 125.2, 125.3, 125.5, 125.8, 126.6, 126.7, 127.1, 127.9, 130.0, 130.8, 131.0, 134.5, 143.6, 149.3, 157.7(Carom), 171.2 (COOH). IR (cm−1): υ 3314, 3044, 1678, 1397, 779, 719. MS (EI): MSD 297 (M+).

Anal. Calcd. for C20H13NO2: C, 80.25; H, 4.38; N, 4.68. Found: C, 80.21; H, 4.44; N, 4.60.

4.1.1.4
4.1.1.4 2-(6-methoxynaphthalen-2-yl)quinoline-4-carboxylic acid 11

Orange solid; yield 25%, mp 149–151 °C, Lit. 258–259 °C (Buu-Hoï, 1949), crystallized from cyclohexane. 1H NMR (DMSO‑d6): δ 3.9 (3H, s, OCH3), 7.21–7.29 (3H, m, Ph-H), 7.39–7.45 (3H, m, Ph-H), 7.92 (2H, t, Het-H), 8.07 (1H, d, J = 8.7 Hz, Het-H), 8.30 (1H, d, J = 8.7 Hz, Het-H), 8.69 (1H, s, Het-H). 13C NMR (DMSO‑d6): δ 55.3 (OCH3), 106.3, 113.8, 115.6, 119.3, 120.9, 124.2, 125.7, 127.5, 127.9, 130.3, 131.1, 131.6, 136.1, 151.6, 158.7, 159.8 (Carom), 160.5 (COOH). IR (cm−1): υ 3468, 3002, 1689, 1477, 1032, 758, 694. MSD 119.1 (M+).

Anal. Calcd. for C21H15NO3: C, 76.58; H, 4.59; N, 4.25. Found: C, 76.54; H, 4.57; N, 4.28.

4.1.1.5
4.1.1.5 2-(phenanthren-3-yl)quinoline-4-carboxylic acid 14

A mixture of 3.4 mmoles (0.5 g) of isatine and 7.1 mmoles (1.5 g) of 3-acetyl-phenanthrene in 20 mL 20% KOH was stirred at reflux temperature for 7 h. The reaction mixture was cooled to rt and concd HCl was added to pH 6.5 and the crystalline solid was filtered and crystallized from i-PrOH.

White solid; yield 54%, mp 261–263 °C, Lit. 268 °C (Buu-Hoï, 1943). 1H NMR (600 MHz, CDCl3): δ 7.70–7.80 (3H, m), 7.90–7.96 (3H, m), 8.04 (1H, d, J = 7.8 Hz), 8.19 (1H, d, J = 8.3 Hz), 8.30 (1H, d, J = 8.3 Hz), 8.62 (2H, t), 8.83 (1H, s), 9.13 (1H, d, J = 8.2 Hz), 9.68 (1H, s). 13C NMR (151 MHz, CDCl3): δ 120.0, 122.5, 123.8, 125.8, 126.1, 126.9, 127.6, 127.7, 128.4, 128.7, 129.1, 129.7, 130.0, 130.4, 130.5, 130.9, 132.3, 133.1, 136.4, 138.9, 148.5, 156.3 (Carom), 168.2 (COOH). IR (cm−1): υ 3435, 3065, 1717, 1630, 1589, 847, 717. MSD 349 (M+).

Anal. Calcd. for C24H15NO2: C, 82.50; H, 4.33; N, 4.01. Found: C, 82.53; H, 4.31; N, 3.98.

4.1.2

4.1.2 Diarylquinolines (DARQ)

4.1.2.1
4.1.2.1 General procedure for compounds 16–23

A mixture of the corresponding aniline (0.51–1.39 g, 5.5 mmoles), arylaldehyde (0.55–0.79 g, 5.25 mmoles), substituted acetophenone (0.66–0.82 g, 5.5 mmoles) and 1% of catalyst placed in a 50 mL round-bottomed flask was subjected to MW irradiation at 400 W and 250 °C. After completion of the reaction (TLC), the reaction mixture was allowed to cool. It was diluted with CH2Cl2 (15 mL) and washed with water, 5% HCl (10 mL) and brine (10 mL). This was then dried (Na2SO4) and concentrated in vacuo to give a solid product which was crystallized from the corresponding solvent. The yields are shown in Table 1.

4.1.2.2
4.1.2.2 2-(3,4-methylenedioxyphenyl)-4-phenylquinoline 18

Pale yellow solid, mp 149–151 °C, crystallized from cyclohexane. 1H NMR (600 MHz, CDCl3): δ 6.05 (2H, s), 6.87 (1H, d, J = 6.9 Hz), 7.15 (1H, d, J = 8.0 Hz), 7.19 (1H, s), 7.20 (1H, s), 7.39 (1H, d, J = 15.5 Hz), 7.52 (2H, t), 7.60 (1H, t), 7.76 (1H, d, J = 15.5 Hz), 8.03 (2H, d, J = 8.1 Hz). 13C NMR (151 MHz, CDCl3): δ 101.6 (OCH2O), 106.7, 108.7, 120.1, 125.2, 128.4, 128.6, 129.4, 132.6, 138.4, 144.7, 148.4, 149.9 (Carom). IR (cm−1): υ 3062, 2913, 1674, 1456, 1260, 804, 717. MS (EI): 325 (M+), 252 (100%), 122 (21%), 77 (26%).

Anal. Calcd. for C22H15NO2: C, 81.21; H, 4.65; N, 4.30. Found: C, 81.23; H, 4.63; N, 4.34.

4.1.2.3
4.1.2.3 4-(4-hydroxyphenyl)-2-phenylquinoline 20

White solid, mp 174–175 °C, crystallized from CH2Cl2. 1H NMR (CDCl3): δ 6.57–6.62 (3H, m), 6.68 (2H, d, J = 8.2 Hz), 6.69 (1H, s), 7.15 (2H, d, J = 7.9 Hz), 7.35 (1H, s), 7.42 (2H, d, J = 8.1 Hz), 7.83 (2H, d, J = 7.9 Hz), 7.79 (2H, d, J = 8.1 Hz). 13C NMR (CDCl3): δ 116.8, 119.8, 122.5, 124.8, 125.5, 126.9, 129.8, 130.0, 131.2, 132.6, 143.7, 146.2, 147.8 (Carom), 159.8 (Carom-OH). IR (cm−1): υ 3300, 3010, 1594, 1485, 1283, 834, 751, 699. MS (EI): 297 (M+), 182 (100%), 121 (36%), 93 (50%), 77 (22%).

Anal. Calcd. for C21H15NO: C, 84.82; H, 5.08; N, 4.71. Found: C, 84.79; H, 5.10; N, 4.67.

4.1.2.4
4.1.2.4 2,4-diphenyl-6-(4-sulfonamido-5-methylisoxazol-3-yl)quinoline 23

White solid, mp 222–223 °C, crystallized from EtOH. 1H NMR (DMSO‑d6): δ 2.51 (3H, s), 6.07 (1H, s), 6.59 (2H, d, J = 8.8), 7.67–7.20 (10H, m), 7.98 (2H, d, J = 7.2 Hz), 10.94 (1H, s). 13C NMR (DMSO‑d6): δ 12.5 (CH3), 112.1, 125.2, 127.0, 127.5, 128.5, 128.9, 129.1, 133.7, 137.1, 143.4 (Carom). IR (cm−1): υ 3369, 3283, 3109, 3065, 1674, 1587, 1174, 1087, 760, 696. MS (EI): 442 (M+), 207 (100%), 162 (31%), 92 (32%), 77 (24%).

Anal. Calcd. for C25H19N3O3S: C, 68.01; H, 4.34; N, 9.52. Found: C, 68.05; H, 4.31; N, 9.55.

4.1.3

4.1.3 Polycyclic quinolines

4.1.3.1
4.1.3.1 General procedure for compounds 26–43

A neat mixture of 1.00 mmol of 2-amino-5-chlorobenzophenones (0.23–0.27 g) or 2-amino-5-nitrobenzophenones (0.24–0.28 g) 24 and 1.50 mmol of the corresponding cyclanone or methylketone (0.15–0.26 g) 25 with 0.15 mL TFA was subjected to MW irradiation, at 400 W and 250 °C. The completion of the reaction was determined by TLC (Muscia et al., 2014). The product was crystallized from EtOH and the reaction times were 2–6 min.

4.1.3.2
4.1.3.2 2-chloro-11-(2-chlorophenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinoline 27

White solid, yield 63%, mp 151–153 °C, crystallized from EtOH. 1H RMN (600 MHz, CDCl3): δ 1.56–1.72 (m, 2H, CH2), 1.87 (s, 4H, CH2), 2.58–2.70 (m, 2H, CH2), 3.26–3.33 (m, 2H, CH2), 7.10 (s, 1H, H-Het), 7.19 (dd, J = 1.4; J = 7.3 Hz, 1H, H—Ar), 7.41–4.48 (m, 2H, H—Ar), 7.56 (dd, J = 2.2; J = 8.9 Hz, 1H, H—Ar) 7.60 (d, J = 7.8 Hz, 1H, H—Ar), 7.99 (d, J = 8.9 Hz, 1H, H-Het).13C NMR (151 MHz, CDCl3): δ 26.9 (CH2), 27.8 (CH2), 30.9 (CH2), 31.9 (CH2), 40.2 (CH2), 124.4, 127.1, 129.2, 129.7, 129.9, 130.4, 131.0, 131.7, 133.7, 135.2, 135.8, 141.8, 144.3, 165.1 (Carom). IR (cm−1): υ 3044, 2918, 2841, 1575, 1468, 1169, 829, 757. MSD 342 (M+).

Anal. Calcd. for C20H17Cl2N: C, 70.18; H, 5.01; N, 4.09. Found: C, 69.85; H, 4.96; N, 4.11.

4.1.3.3
4.1.3.3 7-nitro-9-phenyl-3,4-dihydroacridin-1(2H)-one 33

Yellow solid; yield 35%, mp 195–197 °C, crystallized from EtOH. 1H RMN (CDCl3): δ 2.25–2.37 (m, CH2, 2H), 2.78 (t, CH2, J = 6.7 Hz, 2H), 3.44 (t, CH2, J = 6.2 Hz, 2H), 7.19–7.23 (m, 2H, H-Ph), 7.54–7.59 (m, 3H, H-Ph), 8.21, (d, J = 9.2 Hz, 1H, H-Het), 8.44 (s, 1H, H-Het), 8.53 (d, J = 9.2 Hz, 1H, H-Het). 13C NMR (CDCl3): δ 21.0 (CH2), 34.8 (CH2), 40.5 (CH2), 124.9, 125.0, 125.3, 126.8, 128.0, 128.5, 130.5, 145.6, 150.5, 153.2, 166.1 (Carom), 197.1 (C⚌O). IR (cm−1): υ 3000, 2890, 1696, 1616, 1554, 1338, 714, 688. MSD 113.1 (M+).

Anal. Calcd. for C19H14N2O3: C, 71.69; H, 4.43; N, 8.80. Found: C, 71.47; H, 4.50; N, 8.50.

4.1.3.4
4.1.3.4 8-chloro-10-phenyl-11H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-b]quinoline 35

Pale yellow solid; yield 55%, mp 254–256 °C, crystallized from EtOH. 1H RMN (600 MHz, CDCl3): δ 3.72 (s, 2H, CH2), 6.08 (s, 2H, OCH2O), 6.93 (s, 1H, H-Ph), 7.45 (d, J = 7.0 Hz, 2H), 7.54–7.62 (m, 5H, H—Ar), 7.7 (s, 1H, H-Het), 8.12 (d, J = 9.6 Hz, 1H, H-Het).

13C NMR (151 MHz, CDCl3): δ 33.80 (CH2), 101.69 (OCH2O), 101.9, 105.5, 124.6, 126.6, 128.5, 128.9, 129.0, 129.2, 129.4, 130.4, 130.9, 134.1, 134.2, 135.8, 140.5, 142.0, 146.8, 148.1, 150.4, 161.2 (Carom). IR (cm−1): υ 3000, 2900, 1566, 1468, 1331, 1259, 1037, 833, 708. MSD 372.0 (M+).

Anal. Calcd. for C23H14ClNO2: C, 74.30; H, 3.80; N, 3.77. Found: C, 74.69; H, 3.89; N, 3.55.

4.1.3.5
4.1.3.5 8-chloro-10-(2-chlorophenyl)-11H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-b]quinoline 36

Pale yellow solid; yield 60%, mp 250–251 °C, crystallized from EtOH. 1H RMN (600 MHz, CDCl3): δ 3.68 (q, 2H, CH2), 6.10 (s, 2H, OCH2O), 6.96 (s, 1H, H—Ar), 7.35–7.38 (m, 2H, H-Ph), 7.48–7.54 (m, 2H, H-Ph), 7.63–7.66 (m, 2H, H—Ar), 7.73 (s, 1H, H-Het), 8.15 (d, J = 8.9 Hz, 1H, H-Het). 13C NMR (151 MHz, CDCl3): δ 33.5 (CH2), 101.7 (OCH2O), 102.0, 105.6, 124.2, 126.4, 127.2, 129.6, 130.1, 130.5, 130.8, 131.2, 133.3, 134.1, 134.9, 139.3, 140.4, 146.7, 148.2, 150.5, 161.2, 165.4 (Carom). IR (cm−1): υ 3062, 2925, 2847, 1755, 1471, 1428, 1170, 829, 759. MSD 406.0 (M+).

Anal. Calcd. for C23H13Cl2NO2: C, 68.00; H, 3.23; N, 3.45. Found: C, 67.88; H, 3.17; N, 3.38.

4.1.3.6
4.1.3.6 2-(benzo[d][1,3]dioxol-5-yl)-6-chloro-4-(2-fluorophenyl)quinoline 37

Pale yellow solid; yield 50%, mp 133–135 °C, crystallized from EtOH. 1H RMN (600 MHz, CDCl3): δ 6.04 (s, 2H, OCH2O), 6.86 (d, J = 8.4 Hz, 1H, H—Ar), 7.44–7-52 (m, 3H, H—Ar), 7.61–7.68 (m, 2H, H—Ar), 7.81 (dd, J = 2.3 Hz, J = 9.0 Hz, 1H, H-Ph),7.93 (d, J = 5.5 Hz, 2H, H-Het), 8.16 (d, J = 8.7 Hz, 2H, H-Het). 13C NMR (151 MHz, CDCl3) δ 101.6, 106.7, 108.7, 120.1, 125.2, 128.4, 128.6, 129.4, 132.6, 138.4, 144.7, 148.4, 149.9 (Carom). IR (cm−1): υ 3067, 2897, 2775, 1592, 1481, 1446, 1251, 1038, 873, 764. MSD 378.0 (M+).

Anal. Calcd. for C22H13ClFNO2 C, 69.94; H, 3.47; N, 3.71. Found: C, 70.04; H, 3.50; N, 3.67.

4.1.3.7
4.1.3.7 2-(benzo[d][1,3]dioxol-5-yl)-6-chloro-4-phenylquinoline 38

Pale yellow solid; yield 61%, mp 142–144 °C, crystallized from EtOH. 1H RMN (DMSO‑d6): δ 6.12 (s, 2H, OCH2O), 7.08 (d, J = 8.1 Hz, 1H, H—Ar), 7.50–7.63 (m, 5H, H—Ar), 7.73 (d, J = 2.0 Hz, 1H, H3C6OCH2O), 7.80 (dd, J = 2.1 Hz; J = 8.9 Hz; 1H, H3C6OCH2O), 7.92 (d, J = 6.3 Hz, 2H, H-Het), 8.05 (s, 1H, H-Het), 8.13 (d, J = 8.9 Hz, 1H, H-Het). 13C NMR (DMSO‑d6): δ 102.0 (OCH2O), 107.8, 109.0, 119.9, 122.5, 124.3, 126.2, 129.3, 130.0, 130.8, 131.3, 132.2, 132.9, 137.3, 146.9, 148.3, 148.6, 149.4, 156.13 (Carom). IR (cm−1): υ 3049, 2890, 1589, 1505, 1483, 1369, 1245, 1037, 827, 776, 700. MSD 360.0 (M+).

Anal. Calcd. for C22H14ClNO2: C, 73.44; H, 3.92; N, 3.89. Found: C, 73.65; H, 3.89; N, 3.93.

4.1.3.8
4.1.3.8 2-(benzo[d][1,3]dioxol-5-yl)-6-chloro-4-(2-chlorophenyl)quinoline 39

Pale yellow solid; yield 55%, mp 166–168 °C, crystallized from EtOH. 1H RMN (DMSO‑d6): δ 6.14 (s, 2H, OCH2O), 7.08 (d, J = 8.5 Hz, 1H, H—Ar), 7.30 (s, 1H, H3C6OCH2O), 7.47–7.50 (m, 3H, H—Ar), 7.72–7.82 (m, 2H, H—Ar), 7.93 (d, J = 6.3 Hz, 2H, H-Het), 8.12–8.30 (m, 2H-Het). 13C NMR (DMSO‑d6): δ 102.4 (OCH2O), 107.7, 109.0, 120.4, 122.6, 124.1, 126.3, 128.1, 130.2, 131.0, 131.2, 131.5, 132.2, 132.6, 132.7, 136.0, 145.8, 146.5, 148.6, 149.5, 156.2 (Carom). IR (cm−1): υ 3086, 2879, 2776, 1602, 1472, 1246, 1036, 820, 759. MSD 394.0 (M+).

Anal. Calcd. for C22H13Cl2NO2: C, 67.02; H, 3.32; N, 3.55. Found: C, 68.92; H, 3.36; N, 3.61.

4.1.3.9
4.1.3.9 2-(benzo[d][1,3]dioxol-5-yl)-6-nitro-4-phenylquinoline 40

Pale yellow solid; yield 58%, mp 195–197 °C, crystallized from EtOH. 1H NMR (DMSO‑d6): δ 6.15 (s, 2H, OCH2O), 7.09 (d, J = 8.1 Hz, 1H, H3C6OCH2O), 7.57–7.70 (m, 5H, H-Ph), 7.95–8.02 (m, 2H, H3C6OCH2O), 8.20 (s, 1H, H-Het), 8.26 (d, J = 9.2 Hz, 1H, H-Het), 8.47 (d, J = 9.2 Hz, 1H, H-Het), 8.64 (s, 1H, d, H-Het). 13C NMR (CDCl3): δ 102.2 (OCH2O), 108.0, 109.1, 120.5, 122.8, 123.4, 123.6, 124.3, 130.2, 131.8, 132.3, 136.8, 145.1, 148.7, 150.1, 150.7, 150.9, 158.9 (Carom). IR (cm−1): υ 3082, 3049, 2901, 1592, 1506, 1484, 1339, 1038, 811, 703. MSD 371.0 (M+).

Anal. Calcd. for C22H14N2O4: C, 71.35; H, 3.81; N, 7.56. Found: C, 71.30; H, 3.78; N, 7.60.

4.1.3.10
4.1.3.10 2-(benzo[d][1,3]dioxol-5-yl)-4-(2-chlorophenyl)-6-nitroquinoline 41

Pale yellow solid; yield 55%, mp 259–260 °C, crystallized from EtOH. 1H NMR (600 MHz, DMSO‑d6): δ 6.10 (s, 2H, H24), 6.98 (d, J = 8.2 Hz, 1H, H19), 7.46 (dd, J = 1.5 Hz, J = 7.5 Hz, 1H, H12), 7.51 (dt, J = 1.0 Hz, J = 7.5 Hz, 1H, H13), 7.56 (dt, J = 1.5 Hz, J = 8.0 Hz, 1H, H14), 7.66 (d, J = 8.8 Hz, 1H, H15), 7.77 (dd, J = 1.6 Hz, J = 8.2 Hz, 1H, H18), 7.85 (d, J = 1.6 Hz, 1H, H22), 7.89 (s, 1H, H9), 8.31 (d, J = 9.2 Hz, 1H, H3), 8.44 (d, J = 2.4 Hz, 1H, H6), 8.50 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H, H2). 13C NMR (151 MHz, CDCl3): δ 101.67 (OCH2O), 108.0, 108.6, 121.0, 122.6, 122.7, 123.2, 124.7, 127.3, 130.3, 130.7, 131.3, 131.5, 132.7, 133.2, 135.5, 145.3, 148.4, 145.0, 150.7, 159.3 (Carom). IR (cm−1): υ 3083, 2894, 1601, 1496, 1453, 1337, 1245, 1031, 888, 815. MSD 404.0 (M+).

Anal. Calcd. for C22H13ClN2O4: C, 65.28; H, 3.24; N, 6.92. Found: C, 65.33; H, 3.19; N, 6.89.

4.1.3.11
4.1.3.11 6-chloro-2-(phenanthren-3-yl)-4-phenylquinoline 42

Yellow solid; yield 67%, mp 178–180 °C, crystallized from EtOH. 1H RMN (600 MHz, CDCl3): δ 7.59–7.68 (m, 6H), 7.72–7.75 (m, 2H),7.82 (m, 2H) 7.91–7.92 (m, 2H), 8.05 (d, J = 8.2 Hz, 1H), 8.08 (s, 1H, H-Het) 8.29 (d, J = 8.9 Hz, 1H), 8.46 (dd, J = 1.6 Hz; J = 8.2 Hz, 1H, H-Het), 8.91 (d, J = 8.2 Hz ,1H, H-Het), 9.55 (d, J = 1.1 Hz, 1H, H-Het). 13C NMR (151 MHz, CDCl3) δ 120.2, 122.1, 123.0, 124.6, 125.6, 126.6, 126.6, 126.8, 126.9, 128.0, 128.7, 128.8, 128.9, 129.2, 129.5, 129.5, 130.5, 130.6, 130.6, 131.8, 132.3, 132.3, 132.9, 137.1, 137.8, 147.4, 148.6, 157.1 (Carom). IR (cm−1): υ 3005, 2956, 1591, 1544, 1486, 1361, 1153, 849, 748, 705. MSD 416.0 (M+).

Anal. Calcd. for C29H18ClN: C, 83.75; H, 4.36; N, 3.37. Found: C, 83.92; H, 4.39; N, 3.30.

4.1.3.12
4.1.3.12 6-nitro-2-(phenanthren-3-yl)-4-phenylquinoline 43

Yellow solid; yield 50%, mp 235–237 °C, crystallized from EtOH. 1H NMR (CDCl3): δ 7.67 (s, 1H, H—Ar), 7.70–7.88 (m, 8H, H—Ar), 7.96 (d, J = 8.0 Hz, 1H, H-Het), 8.07 (d, J = 8.0 Hz, 1H, H-Het), 8.22 (s, 1H, H-Het), 8.43–8.57 (m, 3H, H—Ar), 8.90–8.93 (m, 2H, H—Ar), 9.62 (s, 1H, H-Het). 13C NMR (CDCl3): δ 120.9, 122.6, 122.9, 123.2, 124.9, 125.6, 126.5, 127.0, 128.6, 128.8, 129.2, 129.4, 129.5, 130.5, 131.8, 132.3, 133.4, 136.3, 137.0, 145.4, 151.4, 160.1 (Carom). IR (cm−1): υ 3049, 3022, 1590, 1552, 1482, 1336, 1079, 838, 748, 695. MSD 427.1 (M+).

Anal. Calcd. for C29H18N2O2: C, 81.67; H, 4.25; N, 6.57. Found: C, 81.62; H, 4.28; N, 6.54.

4.1.4

4.1.4 General procedure for compounds 44–45

A mixture of the corresponding aniline (0.50–0.52 mL, 5.5 mmoles), piperonal (0.79 g, 5.25 mmoles), 3-acetylindole or acetophenone (0.87–0.66 g, 5.5 mmoles) with 0.15 mL of TFA placed in a 50 mL round-bottomed flask was subjected to MW irradiation at 400 W and 250 °C. After completion of the reaction (TLC) was proceed as described for 16–23.

4.1.4.1
4.1.4.1 2-(benzo[d][1,3]dioxol-5-yl)-4-phenyl-6-(trifluoromethyl)quinoline 45

White solid; yield 49%, mp 115–117 °C, crystallized from EtOH. 1H RMN (600 MHz, CDCl3): δ 6.04 (s, 2H, OCH2O), 6.86 (d, J = 8.0 Hz, 1H, H—Ar), 7.14 (d, J = 7.8 Hz, 1H, H—Ar), 7.19 (s, 1H, H-Het), 7.39 (d, J = 15.6 Hz, 1H, H-Het), 7.52 (t, J = 7.6 Hz, 2H, Ph), 7.59 (t, J = 7.2 Hz, 2H, Ph), 7.76 (d, J = 15.6 Hz, 1H, H-Het), 8.02 (m, 3H). 13C NMR (151 MHz, CDCl3): δ 101.6 (OCH2O), 106.7, 108.7, 120.1, 125.2 (CF3), 128.4, 128.6, 129.4, 132.6, 138.4, 144.7, 148.4 (Carom), 149.93 (Carom-CF3). IR (cm−1): υ 3036, 2922, 2785, 1660, 1590, 1503, 1450, 1253, 1018, 844, 777, 699, 598. MSD 392.0 (M+).

Anal. Calcd. for C23H14F3NO2: C, 70.23; H, 3.59; N, 3.56. Found: C, 70.19; H, 3.62; N, 3.50.

4.2

4.2 In vitro activity against M. tuberculosis (Mtb)

4.2.1

4.2.1 Minimal inhibitory concentration (MIC)

The MIC of compound was determined by measuring bacterial growth after 5 d in the presence of test compounds. Compounds were prepared as 20-point two-fold serial dilutions in DMSO and diluted into 7H9-Tw-OADC medium in 96-well plates with a final DMSO concentration of 2%. The highest concentration of compound was 200 µM where compounds were soluble in DMSO at 10 mM. For compounds with limited solubility, the highest concentration was 50X less than the stock concentration e.g. 100 µM for 5 mM DMSO stock, 20 µM for 1 mM DMSO stock. Control compounds were prepared as 10-point two-fold dilution series. Each plate included assay controls for background (medium/DMSO only, no bacterial cells), zero growth (100 µM rifampicin) and maximum growth (DMSO only), as well as a rifampicin dose response curve. Plates were inoculated with M. tuberculosis and incubated for 5 days: growth was measured by OD590 and fluorescence (Ex 560/Em 590) using a BioTek™ Synergy 4 plate reader. Growth was calculated separately for OD590 and RFU. To calculate the MIC, the dose response curve was plotted as % growth and fitted to the Gompertz model using GraphPad Prism 5. The MIC was defined as the minimum concentration at which growth was completely inhibited and was calculated from the inflection point of the fitted curve to the lower asymptote (zero growth). In addition, dose response curves were generated using the Levenberg-Marquardt algorithm and the concentrations that resulted in 50% and 90% inhibition of growth were determined (IC50 and IC90 respectively).

4.2.2

4.2.2 Minimal bactericidal concentration (MBC)

M. tuberculosis was grown aerobically to logarithmic phase and inoculated into liquid medium containing four different compound concentrations with a final maximum concentration of 2% DMSO. For compounds with an MIC (from Task Group 1 assay), the concentrations selected were 10X MIC, 5X MIC, 1X MIC, and 0.25X MIC. For compounds with MIC > 20 µM, fixed concentrations of 200, 100, 20 and 5 µM were used (assuming solubility to 10 mM in DMSO). Cultures were exposed to compounds for 21 days and cell viability measured by enumerating colony forming units on agar plates on day 0, 7, 14 and 21. MICs were calculated as the average of the MIC derived from RFU and OD from Assay Group 1.

MBC was defined as the minimum concentration required to achieve a 2-log kill in 21 days. For compounds with >1-log kill, an assessment of time- and/or concentration-dependence was determined from the kill kinetics. DMSO was used as a positive control for growth.

4.2.3

4.2.3 Low-oxygen recovery assay (LORA)

Test compounds were prepared as 20-point two-fold serial dilutions in DMSO and diluted into DTA medium in 96-well plates with a final DMSO concentration of 2%. The highest concentration of compound was 200 µM where compounds were soluble in DMSO at 10 mM. For compounds with limited solubility, the highest concentration was 50X less than the stock concentration e.g. 100 µM for 5 mM DMSO stock, 20 µM for 1 mM DMSO stock. Control compounds were prepared as 10-point two-fold serial dilutions in DMSO and diluted into DTA medium in 96-well plates with a final DMSO concentration of 2%.

M. tuberculosis constitutively expressing the luxABCDE operon was inoculated into DTA medium in gas-impermeable glass tubes and incubated for 18 days to generate hypoxic conditions (Wayne model of hypoxia). At this point, bacteria are in a non-replicating state (NRP stage 2) induced by oxygen depletion.

4.2.4

4.2.4 Intracellular drug activity and cytotoxicity

Murine J774 macrophages were infected with a luminescent strain of H37Rv (which constitutively expresses luxABCDE) at a multiplicity of infection of 1. After 18 h, extracellular bacteria were removed by washing and compound was added. Infected macrophages were incubated in the presence of compound for 4 days at 1X and 10X MIC (as determined in aerobic culture in liquid medium from Task 1). For compounds with MIC > 20 µM, fixed concentrations of 20 µM and 200 µM were used. Bacteria were harvested from macrophages by lysis with 0.1% SDS, inoculated into growth media and allowed to grow aerobically for 5 days, when the amount of bacteria present was determined by luminescence. All assays were conducted in triplicate; each assay included a positive control (4 µM isoniazid) and a negative control (2% DMSO). The intracellular activity was expressed as a log reduction of M. tuberculosis using the formula: Log RLU Day 4 Compound - Log RLU Day 4 DMSO

As a control for each assay, the inoculum was plated into 96-well plates, grown for 5 days and luminescence measured; correlation of RLU and CFU was confirmed for each run (data provided as excel spreadsheet). The baseline of infection was determined by harvesting bacteria from macrophages at day 0 before compound addition and plating for CFU determination in triplicate.

The cytotoxicity of compounds was determined by measuring Vero cell viability growth after 2 d in the presence of test compounds. Compounds were prepared as 10-point three-fold serial dilutions in DMSO. Vero cells were cultured in DMEM containing high glucose and GlutaMAX™, 10% FBS, and 1x of Penicillin-Streptomycin solution. Cells were inoculated into assay plates and cultured for 24 h before compound dilutions were added to a final DMSO concentration of 1%. The highest concentration of compound tested was 100 µM where compounds were soluble in DMSO at 10 mM. For compounds with limited solubility, the highest concentration was 50X less than the stock concentration e.g. 100 µM for 5 mM DMSO stock, 20 µM for 1 mM DMSO stock. Each plate included staurosporine as a control.

4.3

4.3 QSAR study

The descriptors were from different classes such as autocorrelation descriptors [e.g., autocorrelation (charge)], chi indices descriptors (e.g., chi chain), electrotopological state index descriptors (e.g., atom type electrotopological state), BCUT descriptors, constitutional descriptors (e.g., weight, ring counts) and topological descriptors (e.g., Zagreb index, Wiener numbers). The standard data reduction technique of ‘Principal Component Analysis’ (PCA) was used to reduce the columns of descriptors to the principal components that contain as much of the original information as possible. The first three PCA vectors were added to the study table containing the binary representation of the activity of the molecules (Todeschini and Consonni, 2009).

Acknowledgments

This work was supported by National Institutes of Health and the National Institute of Allergy and Infectious Diseases (USA), Contract N° HHSN272201100009I/HHSN27200001 A08. Financial help was received from Universidad de Buenos Aires (UBACyT 20020120100043BA), Argentina.

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Appendix A

Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2018.10.003.

Appendix A

Supplementary material

The following are the Supplementary data to this article:

Supplementary data 1

Supplementary data 1


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