QUINOLINYL HETEROCYCLES AS ANTIMYCOBACTERIAL AGENTS: DESIGN DIVERSITY-ORIENTED SYNTHESIS, STRUCTURE ACTIVITY RELATIONSHIP AND ACTIVE ANALOGUES OPTIMIZATION Thesis Submitted To Department of Chemistry Kakatiya University, Warangal For the degree of Doctor of Philosophy in Chemistry By Rachakonda Venkatesham, UGC-SRF, Under the Supervision of Dr. A. Manjula, Principal Scientist Crop Protection Chemicals (Organic-II) Division CSIR-I.I.C.T Crop Protection Chemicals Division (Organic-II) CSIR-Indian Institute of Chemical Technology Hyderabad-500607, India July-2014
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QUINOLINYL HETEROCYCLES AS ANTIMYCOBACTERIAL AGENTS:
Figure 4: Classification of quinoline synthesis, based on starting material
Bedaquiline
Figure 2. Extrapolation of isoniazid and bedaquiline
Isoniazid
Figure 5: Synthetic strategy of TMC-207 based analougues
Chapter-I
Design, diversity-oriented synthesis and structure activity
relationship studies of quinolinyl heterocycles as
antimycobacterial, antimicrobial and anti-inflammatory agents
Scheme 3: Oxidative condensation for C4 unsubtituted quinoline synthesis
Scheme 8: Synthesis of 2-(2-methylquinolin-3-yl)-5-phenethyl-1,3,4-oxadiazole
Scheme 9: Synthesis of 2-bromo-1-(2-methylquinoln-3-yl)ethanone
Scheme 10
Scheme 11: Synthesis of 3-(dimethylamino)-1-(2-methylquinoline-3-yl)prop-2-one
Scheme 12
Scheme 15: Synthesis of 1-(2-methylquinolin-3-yl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one
Scheme 16: Synthesis of 1-(3-(2-methylquinolin-3-yl)-5-(2,4,6-trimethoxyphenyl)-
4,5-dihydro-1H-pyrazol-1-yl)ethanone
Compound Antimycobacterial activity
(against M. smegmatis strain)
Cytotoxicity activity
(against A549 cells)
a &b MIC(μg/mL) cStd. Dev. dIC50 (μM) Std. Dev
86 >100 - 96.373 20.335
89a 34.97 4.2 144.839 28.677
91 >100 - >200 -
92 >100 - 117.724 32.516
94 >100 - 94.198 18.000
95 14.66 1.25 137.510 4.534
102a 57.87 13.18 170.745 48.263
Rifampicin (Control) 2.08 0.04 ----- ------
Isoniazid (Control) 12.07 0.98 ---- ----
aMycobacterium smegmatis ATCC 14468 (MC2).b Concentration of compounds inhibiting growth by 50%c GI50 values are indicated as mean ± SD (standard deviation) of three independent experiments.dIC50 (μM) against A549 cells
Table 1: Primary antimycobacterial and cytotoxicity screening of diverse quinolinyl
heterocycles
Figure 14: Graphical representation of activity results
Scheme 18: Synthesis of 2,5-disubstituted quinolinyl 1,3,4-oxadiazole (26) derivatives
Scheme 19: Synthesis of N-acyl quinolinyl pyrazoline (16) derivatives
Scheme 20: Synthesis of N-phenyl quinolinyl pyrazoline derivatives
Scheme 21: BDMS catalyzed synthesis of 3-(tetrahydro-2H-pyran-2-yl)pentane-2,4-dione
Scheme 22
Scheme 24: Synthesis of 1-(3-(2-methylquinolin-3-yl)-1H-pyrazol-1-yl)ethanone
A: Compunds, B: MIC (µg/mL), C: Std dev, D: IC50 (µm/mL), a Mycobacterium smegmatis ATCC 14468 (MC2). b Concentration of compounds inhibiting growth by 90 %. c MIC values are indicated as mean ± SD (standard deviation), dIC50
(μg/mL) against A549 cells, X: Rifampicin, Y: Isoniazid
Table 2: Antimycobacterial activity of quinolinyl oxadiazoles pyrazolines and
pyrazoles
Figure 16: Graphical representation of antimycobacterial active compounds
Design and diversity oriented synthesis of novel quinoline containing heterocycles has been
achieved employing simple reaction protocols and common intermediates. Simultaneous screening for
antimycobacterial activity led to the identification of quinolinyl oxadiazole and pyrazole frameworks as
active molecules. The synthetic protocols have been successfully extended for generation of library of
uinolinyl oxadiazoles, pyrazolines and pyrazoles. In all, 40 compounds were tested for antimycobacterial
activity and lead identification gave of 20 active molecules and 3 (8, 12j and 12m) promising
compounds. Further, lowcytotoxic effects of these compounds against A549 cell line underline their
potential as antitubercular agents.
• Finding of this results have been published in Eur. J. Med. Chem. 70 (2013) 536-547
Venkatesham Rachakonda, Manjula Alla, Sudha Sravanti Kotapalli, Ramesh Ummanni
Figure 15: Molecular hybridization approach for structure optimization
Scheme 3. Synthesis of quinolinepyrazolyl 1,2,3-triazole hybridized moecules (21 molecules)
starting from common intermediates 13 and 14
Antimycobacteria
l activity
Cytotoxicity Antimycobacterial
activity
Cytotoxicity
A Ba&b Cc Dd Cc A Ba&b Cc Dd Cc
12a 28.8 0.032 >100 52b 33.76 0.01 36.6 17.52
12b >100 22.16 13.2 52c >100 12.35 0.26
12c 19.57 0.004 >100 52d >100 21.02 1.23
12d 17.26 0.003 >100 52e >100 >100
12e 21.62 0.050 >100 52f NA 23.65 8.13
12f >100 >100 52g >100 >100
12g 23.5 0.038 8.29 6.63 52h >100 15.49 8.71
12h >100 10.86 2.09 52i NA >100
12i 14.92 0.012 15.82 8.29 53a >100 20.44 9.75
12j >100 17.08 11.84 53b 33.27 0.012 16.04 0.75
12k >100 23.85 2.3 53c 25.17 0.013 >100
36 NA 10.52 6.49 53d 26.34 0.004 22.88 15.36
20a >100 24.29 22.97 53e 29.87 0.006 16.442 4.69
20b 20.64 0.06 11.14 5.84 53f >100 22.25 11.79
20c >100 15.19 2.93 53g >100 >100
20d NA >100 53h >100 >100
22 NA >100 54a NA 20.114 6.92
37 28.26 13.19 3.96 54b 40.5 >100
23 >100 15.26 5.92 54c >100 >100
52a NA >100 55 >100 16.85 9.22
X 12.07 ------- X 12.07 -------
Y 2.15 ------- Y 2.15 -------
Z ------- ------- 0.16 Z ------- -------
A: Compound, B: MIC (µg/mL), C: STD Dev; aMycobacterium smegmatis ATCC 14468 (MC2155).b Minimum concentration of compounds inhibiting visible bacterial growth. c MIC values are indicated as mean ±SD (standard deviation) of
three independent. d IC50 (µg/mL) against A549 cells.
X: Isoniazid, Y: Rifampicin, Z: Doxorubicin
Antimycobacterial evaluation of optimized quinolinyl heterocycles
• The MIC values (µg/ml) of compounds 14a (28.8±0.032), 14c (19.57±0.004),
14d (17.26±0.003), 14e (21.62±0.05), 37b (33.76 ± 0.01), 38c (25.17±0.013)
and 39b (40.5) compared to their cytotoxicity in IC50 (>100) highlight that these
are promising scaffolds to design and develop
quinolinyl based antimycobacterial agents.
• 14i showed cytotoxicity with IC50 value 32.70±8.29 µM while its MIC was found
to be 14.92±0.012 (µg/ml).
• Thus, this compound may not be a good antitubercular agent.
• Interestingly quinolinyl hydrazones were shown good antimycobacterial activity
than the corresponding pyrazolyl1,2,3-triazoles.
• It was initiated to gone for antibacterial activity of quinolinyl hydrazone
In vitro antibacterial activity of quinolinyl hydrazones