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Ph.D. work ppt presentation
1. QUINOLINYL HETEROCYCLES AS ANTIMYCOBACTERIALAGENTS:
DESIGN DIVERSITY-ORIENTED SYNTHESIS, STRUCTURE ACTIVITY
RELATIONSHIPAND 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
4. Tuberculosis (TB)
Tuberculosis (TB) is the leading infectious disease in the world.
It is caused by the bacillus Mycobacterium tuberculosis (MTB) and was discovered
by Robert Koch in 1882.
Latent TB
Drug sensitive Tuberculosis-curable with first line drugs (INH, PZA, EMB, RIF)
MDR-TB-resistant to RIF and INH, treatment FQs & inject able drugs AMK,
KAN, CAP.
XDR-TB resistant to at least one FQs and inject able drugs
TDR-TB incurable form of TB
HIV- Co-Infection
DOTS strategy
BCG-Vaccination
5. Figure 2: M. tuberculosis aerosol transmission and progression to infectious TB or
non-infectious (latent) disease
40. 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
41. Gram negative bacterial strains Gram positive bacterial strains
Comp a b c d e f g h i j
89n -- -- -- -- 0.14 0.14 0.13 -- -- --
89r -- 0.14 -- 0.13 -- -- -- -- -- --
89s 0.14 -- -- 0.13 0.11 -- 0.11 0.14 -- --
89w 0.14 -- -- -- -- -- -- -- -- --
89y -- -- -- -- 0.15 -- 0.15 -- -- --
Std -- 0.18 0.22 -- -- 0.18 0.14 0.16 0.22 0.18
Std (Standard): Streptomycin (Concentration 10μg/mL)
a= Eschericha coli, b= Proteus vulgaris, c= Proteus mirabilis, d= Klebsiela
pneumoniae, e= Enterobacter aerogens, f= Bacillus subtilis, g= Bacillum
megaterium, h= Bacillus pumilis, i= Staphylococcus aureus, j= Streptococcus
pyogens and-- = Not active
Antibacterial activity (MIC 10µg/mL) of 2-(2-methylquinolin-3-yl)-5-substituted-1, 3, 4-oxadiazoles
Five of the seventeen
compounds tested showed
impressive MIC values
(10μg/mL). Compounds 89w,
89s showed effective inhibition
on E. coli at 10µg/mL
concentration. Compounds 82r,
82s and 89n, 89s, 89y showed
effective inhibition on Klebsiella
pneumoniae and Enterobacter
aerogenes, at 10µg/mL
concentration, respectively. At
this concentration (10μg/mL),
standard has not shown any
inhibition of these species.
Among all the tested
compounds, 89w, 89n, 89r, 89s,
89y effectively inhibited the
growth of resistant gram
negative bacteria compared to
gram positive bacteria at
10µg/mL concentration
42. Antifungal activity of 2-(2-methylquinolin-3-yl)-5-substituted-1, 3, 4-oxadiazoles
Zone of inhibition ( mm)
A B a b c d A B a b c d
89a
600 4.50 5.03 7.59 5.56
89o
600 NA 4.35 3.54 5.09
900 8.45 10.73 14.45 10.67 900 NA 8.45 6.23 10.45
89b
600 4.26 5.35 3.32 5.92
89q
600 5.56 4.32 7.65 6.32
900 7.72 10.85 6.54 11.23 900 11.05 8.25 14.34 12.35
89c
600 5.05 6.32 6.59 6.90
89r
600 6.25 4.05 3.50 3.45
900 10.23 13.16 14.12 13.06 900 12.24 8.25 6.45 6.56
89d
600 5.32 5.56 4.56 3.23
89s
600 4.56 6.32 8.56 4.45
900 10.82 11.32 8.89 6.67 900 8.23 12.34 16.24 9.05
89e
600 3.34 5.54 4.34 2.12
89v
600 4.12 5.03 5.23 4.05
900 6.21 10.21 8.21 4.34 900 8.45 10.34 10.56 8.10
89f
600 3.42 4.26 3.25 3.45
89w
600 5.65 4.45 3.32 5.56
900 6.75 8.59 6.50 7.14 900 10.25 9.08 6.67 10.54
89g
600 3.12 4.98 3.92 5.39
89I
600 2.13 5.32 6.87 5.23
900 6.23 9.43 7.42 11.12 900 4.32 10.64 12.21 10.54
89n
600 6.50 6.25 NA 5.35
……..
……… ……… ……… ……… ……….
900 12.23 12.87 NA 11.05 ……… ……… ……… ……… ………
X
600 5.35 10.80 7.56 9.34
X
600 5.35 10.80 7.56 9.34
900 12.01 20.03 14.76 18.26 900 12.01 20.03 14.76 18.26
a=Candida albicans, b=Fusarium oxysporium, c=Dreschleria halides, d=Colletotrichum falcatum; NA=No Activity; B: Itraconazole
(Standard)
An extra heterocycle substitution on oxadiazole enhances the antifungal activity. 3-[5-(4-
Methoxyphenyl)-[1,3,4]oxadiazol-2-yl]2-methylquinoline (89r) is the other compound which
inhibited fungal growth to significant extent.
43. Table 7: Anti-inflammatory activity of 2-(2-methylquinolin-3-yl)-5-substituted-1, 3, 4-oxadiazoles by
carrageenan-induced rat paw edema assay (acute inflammatory model)
Comp Dose
(mg/kg)
Percentage of Edema Inhibition
(%)
30 mins 1h 2h 3h
89b 100 28 35.2 51.6 51.7
89c 100 24 35.2 60 49.4
89d 100 16 26.4 28 24.1
89f 100 32 38.2 57.3 48.2
89g 100 16 35.2 45.3 24.1
89n 100 40 41.1 60 67.8
89o 100 36 44.1 54.6 58.6
89q 100 20 35.2 41.3 42.5
89r 100 12 17.6 40 42.5
89y 100 20 38.2 56 50.5
89I 100 36 50 50.6 57.4
Std
(Diclofenac)
10 40 41.1 52 68.9
The anti-inflammatory activity profile indicates that compounds with heterocyclic substitution at 5th
position of oxadiazole is again the best candidate among the tested molecules. Thiophene substitution
shows better anti-inflammatory activity than standard at 1 h, 2 hrs, 3 hrs time but activity falls at 4
hrs, while in case of pyrazole substitution activity falls from 3 hrs. 2-(2-Methylquinolin-3-yl)-5-(1-
phenylethyl)-1,3,4-oxadiazole (89b) is the only alkyl substitution that exhibits good activity.
44. Chapter-III
Quinolinyl Heterocycles as Antimycobacterial Agents: Towards
Structure Optimization of the Acive Analogues 2-Methyl-3-(1H-
pyrazol-5-yl)quinoline and 3-(5-(2-methylquinolin-3-yl)-1,3,4-
oxadiazol-2-yl)4H-chromen-4-one
45. In all, 40 compounds were tested for antimycobacteium activity and lead identification
gave of 20 active molecules and 2 (1, 2) promising compounds
Compound MIC(μg/mL)
2 14.66
Rifampicin (Control) 2.08
Isoniazid (Control) 12.07
Compound MIC(μg/mL)
1 16.83
Rifampicin(Control) 2.15
Isoniazid (Control) 11.78
56. Scheme 10: Synthesis of 2-methyl-3-(1-(prop-2-ynyl)-1H-pyrazol-3-yl)quinoline or
ethyl 3-(2-methylquinolin-3-yl)-1-(prop-2-ynyl)-1H-pyrazole-4-carboxylate
58. Scheme 3. Synthesis of quinolinepyrazolyl 1,2,3-triazole hybridized moecules (21 molecules)
starting from common intermediates 13 and 14
59.
60.
61.
62.
63. 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
64. • 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
65. In vitro antibacterial activity of quinolinyl hydrazones
MIC (10μg/mL)
Gram Negative bacterial strains Gram Positive bacterial strains
Comp a b c d e f g h i j
12a 0.14 -- -- 0.11 -- -- 0.11 -- -- --
12b -- -- -- -- 0.15 0.15 -- 0.12(
25)
-- --
12c 0.11 -- -- -- 0.14 0.14 0.12 - -- --
12d 0.14 -- -- 0.13 0.11 -- 0.11 014 -- --
12e -- -- -- -- 0.14 -- 0.13 -- -- --
12f -- -- -- -- 0.15 -- 0.15 -- -- --
Std --- 0.18 0.22 --- --- 0.18 0.14 0.16 0.22 0.18
Std (Standard): Streptomycin a= Eschericha coli, b= Proteus vulgaris, c= Proteus mirabilis,
d= Klebsiela pneumoniae, e= Enterrobacter aerogens, f= Bacillus subtilis, g= Bacillum
megaterium, h= Bacillus pumilis, i= Staphylo coccusaureus, j= Streptococcus pyogens and -
-- Not Active.
Six of the ten
compounds tested showed
impressive MIC values
compared to streptomycin
which was used as standard
(10μg/mL) on different strains.
Among all the tested
compounds, 12(a-f) effectively
inhibited the growth of drug
resistant gram negative bacteria
compared to gram positive
bacteria at 10µg/mL
concentration. Graphical
representation of antibacterial
activity of quinolinyl
hydrazones in MIC is shown
66. • Selective structure optimization of the hits was attempted on 3-(5-(2-methylquinolin-
3-yl)-1,3,4- oxadiazol-2-yl)-4H-chromen-4-one and 2-methyl-3-(1H-pyrazol-5-
yl)quinoline molecules by both forward and reverse synthetic approaches.
• Molecular hybridization of 2-methyl-3-(1H-pyrazol-5-yl)quinoline employing the
copper catalyzed Huisgen’s 1,3-dipolar cycloaddition (Click reaction) led to
introduction of 1,2,3-triazole ring.
• 40 compounds synthesized were evaluated for their antimycobacterial activity and
cytotoxicity against A549 cell line.
• All Among the 14 antitubercular active compounds, 3 have shown promising activity
coupled with low cytotoxicity profile.
• Quinolinyl hydrazones were also evaluated for anti bacterial activity which shown
good results
• Finding of this results have been Communicated to
Eur. J. Med. Chem. Venkatesham Rachakonda, Manjula Alla, Sudha Sravanti
Kotapalli, Ramesh Ummanni, Ramakrishna Munnaluri, Yamini Lingala, Vijjulatha
Manga.
Results
85. Total 129 compounds were synthesized. Design, diversity oriented synthesis of
bedaquiline related N-heterocycles were succesfully achieved and evaluated against
M.smegmatis strain for anti TB activity. Based on hits observed, lead generation, SAR and
structure optimization was carried out. In all 100 novel quinolinyl heterocycles, 80
compounds were tested for antimycobacterial activity 34 active and 6 promising
compounds were observed. Low cytotoxocity of the compounds highlighted their
efficiency. In addition to this, these compounds also having good antimicrobial as well as
anti-inflammatiry activities. Synthesis of imidazo[1,2-a]pyridine derivatives (16
compounds) were completely studied and a variety of cyclic, acyclic quinolinyl derivatives
(21 compounds) were achieved under solvent free conditions without involving tedious
purification techniques
Conclusions
Ihe End
But journey will
cotinue…………
86. Acknowledgemen
ts• Dr. A. Manjula, Principal Scientist, Supervisor, CPC Division
CSIR-IICT
• Dr. B. Vittal Rao, Retired Scientist, CPC Division CSIR-IICT
• Head CPC and DIICT
• Proff. V. Ravinder, Head, Dept of Chemistry, KU
• Proff. G. Dayakar, Chairmen, BOS, Dept of Chemistry, KU
• Proff Sadanandam, Dean Faculty of Science
• Teaching Staff Kakatiya University
• Proff. K. Rajareddy, KITS Warangal
• Proff. Komal Reddy, Dean Faculty of Science, Satavahana University, Karimnagar
• Proff. M. Thirumala Chary, Chairmen, BOS, JNTU Hyderabad
• Dr. Madhukar Reddy, KITS Warangal
• Dr. Ramesh Babu, KITS Warangal
• Dr. D. Prabhakara Chary, KITS Warangal
• Dr. Ranadeer Kumar, KITS Warangal
• S. Ramakrishna Reddy (Degree Lecturer)
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