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New semi-synthetic derivatives of camphor and evaluation for their growth
inhibitory potential against drug resistant pathogens and Earthworms
Dr. M. Geethavani, M. Pharm., PhD
Professor & HOD
Department of pharmaceutical Chemistry
Balaji college of Pharmacy
Ananthapuramu, Andhra Pradesh State, INDIA - 515721
Research work
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There are three types of threats have been classified, the classification is appended
below,
A)Urgent threats:
• Drug resistant Clostridium difficile,
• Carbapenem-resistant Enterobacteriaceae (CRE),
• Drug-resistant Neisseria gonorrhea.
B)Serious Threats
• Multidrug-resistant tuberculosis (MDR-TB),
• drug resistant Acinetobacter, Campylobacter, Pseudomonas, Salmonella, Shigella,
• Methicillin-resistant Staphylococcus aureus (MRSA)
• Extended spectrum β-lactamase producing Enterobacteriaceae (ESBLs),
• Drug-resistant Streptococcus pneumonia,
• Fluconazole-resistant Candida.
C) Concerning Threats
• Vancomycin-resistant Staphylococcus aureus (VRSA),
• Erythromycin-resistant Group A streptococcus,
• Clindamycin-resistant Group B Streptococcus.
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 Camphor is a waxy, white or transparent solid with a strong aromatic odour
which sublimates at room temperature and melts at 180 °C.
 It is practically insoluble in water, but soluble in alcohol, ether, chloroform
and other organic solvents.
 In Asia, a major source of camphor is camphor basil (Ocimum
kilimandscharicum).
 The East African camphorwood tree (Ocotea usambarensis).
 In the 19th century, it was known that nitric acid oxidizes camphor into
camphoric acid, this serves as basis for camphor derivatives.
24-02-2024 Dept. of Pharmaceutical Chemistry 5
 Used as explosive.
 Pest deterrent & preservative.
 Used as culinary.
 Used as flavouring agent.
 Used in cosmetic.
 used externally to relieve arthritic and rheumatic pains, neuralgia, and
back pain.
 It is often used in steam vapourizors to help control coughs by
producing a local anesthetic action to the throat and to loosen
congestion due to colds.
24-02-2024 Dept. of Pharmaceutical Chemistry 6
 The rapid emergences of resistant bacteria jeopardize the efficacy of antibiotics
and have turned out as public threat.
 The Centers for Disease Control and Prevention (CDC) has categorized the drug
resistant pathogens presented as urgent, serious, and concerning threats, which
are playing key role in antibiotic crisis and financial burden not only on
developing countries like India but also to developed nations like USA.
 As per WHO, there should be urgent need of new antibiotics with novel
mechanism to save 10 million people death by 2050.
 Till today only combination therapy was the priority to manage resistance, but
the battle was over.
 Hence, this work was designed to explore possible semi-synthetic derivatives of
camphor by condensation with various potent pharmacophore such as
qunoxiline, Isatin, salicylic acid etc. for antibacterial potential against drug
resistant infections and anthelmintic activity.
24-02-2024 Dept. of Pharmaceutical Chemistry 7
 To explore possible new semi-synthetic derivatives of camphor
through methylene bridge using potent antimicrobial pharmacophore
such as salicylic acid, Isatin, benzoin and qunoxiline.
 To characterize the structures of new compounds with physical and
spectral data.
 To evaluate the antimicrobial / growth inhibitory potential of new
derivatives against drug resistant species.
 To evaluate the anthelmintic activity against earthworms.
 To develop a structure activity relationship for their growth inhibitory
potential against drug resistant pathogens.
 To recommend the future research directions.
24-02-2024 Dept. of Pharmaceutical Chemistry 8
Step 2
Step 3
Step 1  Literature survey.
 Chemical synthesis and Purification.
 Characterization of compounds.
 Screening for antimicrobial / anthelmintic potential.
 Development of Structure activity relationship.
 Make recommendation for further research.
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Then the final product
was subjected to
purification process
Reaction was
monitored by
TLC
The reaction mixture was
heated to 700c and stirred
for 5-8 hours
Qunoxiline 2-dione, salicylic acid, Isatin,
benzoin, biphenyl qunoxiline, biphenyl
amine in to 250 ml beaker containing 100
ml of 35 % HCl and 35 ml of
formaldehyde
GENERAL SYNTHESIS PROCEDURE :-
A mixture of
camphor
(0.015 mol)
24-02-2024 Dept. of Pharmaceutical Chemistry 11
O
N
N
O
N
N
SO2Cl
O
N
N
O
O
N
N
O
O
O
+
O
+
O
N
N
SO2NH2
N
N
SO2NH2
O
+
O
+
N
N
N
N
SO2Cl
REACTIONS OF CHEMICALS WITH CAMPHOR AS GIVEN ABOVE PROCEDURE
ABC-1
ABC-2
ABC-3
ABC-4
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O
HO
O
HO
O
N
H
O
O
O
+
O
+
HO
O
HO
N
H
O
O
O
+
HO
O
O
HO
O
ABC-5
ABC-6
ABC-7
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N
N
O
O
+
+
N
N
SO2NH2
+
+
N
N
N
N
SO2Cl
N
N
O
O
O
S
O
O
OH
N
N
O
S
O
O
OH
SO2NH2
N
N
O
S
O
O
OH
SO2Cl
N
N
O
S
O
O
OH
O
S
O
O
OH
O
S
O
O
OH
O
S
O
O
OH
O
S
O
O
OH
REACTIONS OF CHEMICALS WITH C S A AS GIVEN ABOVE PROCEDURE
XYZ-1
XYZ-2
XYZ-3
XYZ-4
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+
+
HO
O
HO
N
H
O
O
+
HO
O
N
H
O
O
O
S
O
O
OH
O
S
O
O
OH
HO
O
HO
OH
O
O
S
O
O
OH
O
S
O
O
OH
O
S
O
O
OH
O
S
O
O
OH
XYZ-5
XYZ-6
XYZ-7
24-02-2024 Dept. of Pharmaceutical Chemistry 15
Compound
code
Mol. formula Molecular
weight
Melting
point (ᵒc)
Rf value % yield Logp
ABC-1 C19H20N2O3 324.37 133 0.96 89.6 3.01
ABC-2 C31H31N3O3S 525.55 146 0.89 92.9 7.26
ABC-3 C31H30N2O 446.58 127 0.78 85.8 7.8
ABC-4 C31H29ClN2O4S 545.09 155 0.92 91.0 8.25
ABC-5 C25H28O3 376.49 101 0.71 87.8 5.49
ABC-6 C18H22O4 302.36 126 0.53 85.5 4.16
ABC-7 C19H21NO3 311.37 103 0.82 89.8 3.3
XYZ-1 C19H20N2O6S 404.44 117 0.91 95.5 1.4
XYZ-2 C31H31N3O6S2 605.17 112 0.78 92.1 5.26
XYZ-3 C31S30N2O4S 526.65 124 0.63 94.8 6.19
XYZ-4 C31H29ClN2O6S2 625.15 135 0.73 88.5 6.64
XYZ-5 C26H32O6S 472.59 155 0.94 92.6 4.75
XYZ-6 C19H26O7S 398.47 147 0.85 93.5 4.36
XYZ-7 C19H21NO6S 391.44 138 0.72 90.5 1.69
Physical data of the compounds after synthesis
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Compound Code Name
ABC-1 6-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1-yl)methyl)quinoxaline-2,3-
dione
ABC-2 6,7-diphenyl-3-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1-
yl)methyl)quinoxaline-2-sulfonamide
ABC-3 4-((6,7-diphenylquinoxalin-2-yl)methyl)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-one
ABC-4 6,7-diphenyl-3-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1-yl)methyl)
quinoxaline-2-sulfonyl chloride
ABC-5 4-(3-(1-hydroxy-2-oxo-2-phenylethyl)benzyl)-1,7,7-Trimethylbicyclo
[2.2.1]heptan-2-one
ABC-6 2-hydroxy-5-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1-
yl)methyl)benzoic acid
ABC-7 5-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1-yl)methyl)indoline-2,3-
dione
IUPAC nomenclature of the synthesized compounds
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XYZ-1 (4-((2,3-dioxo-2,3-dihydroquinoxalin-6-yl)methyl)-7,7-dimethyl-2-
oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
XYZ-2 6,7-diphenyl-3-((4,7,7-trimethyl-3-oxobicyclo quinoxaline-2-
sulfonamide)[2.2.1]heptan-1-yl)methanesulfonic acid
XYZ-3 (4-((6,7-diphenylquinoxalin-2-yl)methyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]
heptan-1-yl)methanesulfonic acid
XYZ-4 (4-((3-(chlorosulfonyl)-6,7-diphenylquinoxalin-2-yl)methyl)-7,7-dimethyl-
2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
XYZ-5 4-(3-(1-hydroxy-2-oxo-2-phenylethyl)benzyl)-7,7-dimethyl-2-
oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
XYZ-6 2-hydroxy-5-((4,7,7-trimethyl-3-oxobicyclo)methyl)benzoic acid)[2.2.1]
heptan-1-yl)methanesulfonic acid
XYZ-7 (4-((2,3-dioxoindolin-5-yl)methyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-
1-yl)methanesulfonic acid
IUPAC nomenclature of the synthesized compounds
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Compound code IR (ATR) in cm-1
ABC-1 3418,2883,1867,1794,1681,1648,1540,1423,1078
ABC-2 3388,1678,1648,1541,1509,1455,1205,1097,600
ABC-3 3524,1843,1718,1577,1366,1272,1118,1069,741,701,
ABC-4 3612,3564,2819,1793,1627,1143,1049,1021,759,691
ABC-5 3377,2982,1721,1676,1576,1173,1066,1039,971,745,695,672
ABC-6 3648,3616,2865,2590,1721,1660,1437,1281,1122,687,649
ABC-7 3712,2953,1738,1510,1417,1372,1045,749,609
XYZ-1 3403,2942,1650,1635,1520,1039,953,581,581,567
XYZ-2 3673,3211,3009,2940,2328,1698,1951,1698,1288,1175,766,592,563
XYZ-3 3737,3084,2914,2329,1718,1541,1342,1126,759,694,680
XYZ-4 3648,2982,1719,1579,1366,1273,1119,1070,1014,741,693
XYZ-5 3378,2590,1718,1674,1577,1446,1273,1173,1066,744
XYZ-6 3648,3616,2865,2590,1721,1660,1437,1281,1122,687,649
XYZ-7 3311,3049,1729,1612,1326,1464,1148,1095,737,574
IR (ATR, Cm-1) spectral data of synthesized compounds
3500 (-OH), 3200 (NH), 3000 (CH), 1700 (C=O), 1600 (C=C)
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IR Spectra of camphor
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IR Spectra of camphor sulphonic acid
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IR Spectra of benzoin with camphor
Chemical shift value in ppm Protons (type)
3.1 – 3.7 cpx, camphor,
4.3 (-CH2-) methylene bridge
6.9-7.9 (aryl H) Aromatic phenyl protons
10.3 9-(OH). Phenolic hydroxyl
>12 (COOH) Carboxylic acid group
Chemical shift value in ppm Protons (type)
2.3 – 3.9 cpx, camphor,
4.6 (-CH2-) methylene bridge
7.2-8.2 (aryl H) Aromatic phenyl protons
>11 (OH) Sulphonic acid group
H1NMR spectral data of XYZ-5 (Benzoin Derivatives of camphor sulphonic acid):
H1NMR spectra for ABC 6 (salicylic acid Derivatives of camphor):
24-02-2024 Dept. of Pharmaceutical Chemistry 24
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H1NMR spectra for ABC 6 (salicylic acid Derivatives of camphor)
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H1NMR spectral data of XYZ-5 (Benzoin Derivatives of camphor sulphonic acid)
Compound code Mol. Formula Molecular weight Mass e/z value
ABC-1 C19H20N2O3 324.37 325 (M+H)
ABC-2 C31H31N3OS 525.55 327 (M+H)
ABC-3 C31H30N2O 446.58 445 (M-H)
ABC-4 C31H29CLN2O4S 545.09 546 (M+H)
ABC-5 C25H28O3 376.49 377 (M+H)
ABC-6 C18H22O4 302.36 320 (M+18)
ABC-7 C19H21NO3 311.37 313(M+H)
XYZ-1 C19H20N2O6S 404.44 427 (M+23)
XYZ-2 C31H31N3O6S2 605.17 628 (M+23)
XYZ-3 C31S30N2O4S 526.65 527 (M+H)
XYZ-4 C31H29CLN2O6S2 625.15 624 (M-H)
XYZ-5 C26H32O6S 471.59 469 (M-H)
XYZ-6 C19H26O7S 398.47 400 (M+H)
XYZ-7 C19H21NO6S 391.44 390 (M-H)
Mass (ESI) Spectral studies (ESI – Positive & Negative mode)
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Name Description Strain Organism Type
Staphylococcus aureus MRSA ATCC 43300 Bacteria G+ve
Escherichia coli FDA control ATCC 25922 Bacteria G-ve
Klebsiellapneumoniae MDR ATCC 700603 Bacteria G-ve
Acinetobacter baumannii Type strain ATCC 19606 Bacteria G-ve
Pseudomonas aeruginosa Type strain ATCC 27853 Bacteria G-ve
Candida albicans CLSI reference ATCC 90028 Fungi Yeast
Cryptococcus neoformans var.
grubii Type strain
H99; ATCC
208821 Fungi Yeast
Microorganisms used in the study
CLSI : Clinical and laboratory standard institute
MDR : Multiple drugs resistant
MRSA : methicillin resistant Staphylococcus aureus
FDA : Food and drug administration
Place of Screening: Data Provided by CO-ADD Community for Open Antimicrobial Drug
Discovery, Institute for Molecular Bioscience, The University of Queensland, 4072 St Lucia
QLD Australia (Project ID: PO319)
24-02-2024 Dept. of Pharmaceutical Chemistry 31
 Antibacterial data Collection
Inhibition of bacterial growth was determined measuring absorbance at
600 nm (OD600), using a Tecan M1000 Pro monochromator plate reader.
 Growth inhibition of C. albicans was determined measuring absorbance at 530
nm (OD530), while the growth inhibition of C. neoformanswas determined
measuring the difference in absorbance between 600 and 570 nm (OD600-570),
after the addition of reassuring (0.001% final concentration) and incubation at
35 °C for additional 2h.
A - [Active] Samples with inhibition values equal to or above 80% and abs (Z-Score)
above 2.5 for either replicate (n=2 on different plates) were classed as actives.
P - [Partial Active] compounds with inhibition values between 50.9% - 79.9% or abs (Z-
Sore) below 2.5.
I - Inactive compounds with inhibition values below 50% or abs (Z-Sore) below 2.5.
Quality control measures in the study
24-02-2024 Dept. of Pharmaceutical Chemistry 32
Compound
Code
Sa Hit Ec Hit Kp Hit Pa Hit Ab Hit Ca Hit Cn Hit
ABC1 I I I I I I I
ABC2 I I I I I I I
ABC3 I I I I I I I
ABC4 I I I I I I I
ABC5 I I I I I I I
ABC6 I I I I I P I
ABC7 I I I I I I I
XYZ1 I I I I I I I
XYZ2 I I I I I I I
XYZ3 I I I I I I I
XYZ4 I I I I I I I
XYZ5 I I I I I I I
XYZ6 I I I I I I I
XYZ7 I I I I I I I
Summary of the antimicrobial activity (@ 32 µg/ml)
24-02-2024 Dept. of Pharmaceutical Chemistry 33
Compound Code Sa Hit Ec Hit Kp Hit Pa Hit Ab Hit Ca Hit Cn Hit
ABC1 -0.93 -7.73 -0.07 2.95 7.96 4.39 -20.65
ABC2 3.53 1.17 -1.62 6.03 15.80 4.78 -9.63
ABC3 7.26 6.15 10.13 2.01 25.94 9.59 -26.16
ABC4 2.89 5.96 6.80 -7.33 14.33 6.64 -114.97
ABC5 0.12 9.82 10.79 -5.93 17.29 10.10 -103.27
ABC6 -2.89 0.70 8.00 -16.15 8.11 63.29 -97.41
ABC7 39.44 3.87 12.47 9.57 16.92 24.35 -151.11
XYZ1 3.23 4.32 1.59 2.78 7.01 13.50 -28.22
XYZ2 0.93 8.09 9.27 1.23 8.87 7.98 -90.18
XYZ3 2.45 8.03 8.50 -3.61 5.72 6.32 -87.09
XYZ4 7.13 8.38 12.37 0.40 0.28 4.90 -110.15
XYZ5 0.63 3.83 20.09 -1.60 15.06 7.41 -59.20
XYZ6 5.44 0.10 4.13 0.90 11.41 3.94 -11.01
XYZ7 13.71 1.41 9.81 2.58 24.69 7.41 -61.61
% Inhibition data on drug resistant pathogens (@ 32 µg/ml)
24-02-2024 Dept. of Pharmaceutical Chemistry 34
0
10
20
30
40
50
60
70 ABC1
ABC2
ABC3
ABC4
ABC5
ABC6
ABC7
XYZ1
XYZ2
XYZ3
XYZ4
XYZ5
XYZ6
XYZ7
Sa Hit
Ec Hit
Kp Hit
Pa Hit
Ab Hit
Ca Hit
Cn Hit
% Inhibition data on drug resistant pathogens (@ 32 µg/ml)
24-02-2024 Dept. of Pharmaceutical Chemistry 35
Compound Code Sa Hit Ec Hit Kp Hit Pa Hit Ab Hit Ca Hit Cn Hit
ABC1 -0.24 0.99 0.60 -1.30 -0.01 0.26 -0.58
ABC2 -0.82 -0.36 0.82 -2.06 -0.96 0.12 -0.83
ABC3 -1.30 -1.12 -0.85 -1.06 -2.19 -1.58 -0.46
ABC4 -0.74 -1.09 -0.37 1.24 -0.78 -0.53 1.50
ABC5 -0.38 -1.68 -0.94 0.90 -1.14 -1.77 1.24
ABC6 0.00 -0.29 -0.55 3.43 -0.03 -20.72 1.11
ABC7 -5.42 -0.77 -1.18 -2.94 -1.10 -6.84 2.30
XYZ1 -0.78 -0.84 0.36 -1.25 0.09 -2.98 -0.41
XYZ2 -0.48 -1.42 -0.73 -0.87 -0.12 -1.01 0.95
XYZ3 -0.68 -1.41 -0.62 0.32 0.25 -0.42 0.88
XYZ4 -1.28 -1.46 -1.17 -0.66 0.90 0.08 1.39
XYZ5 -0.45 -0.77 -2.27 -0.17 -0.87 -0.81 0.26
XYZ6 -1.06 -0.20 0.00 -0.79 -0.43 0.42 -0.80
XYZ7 -2.12 -0.40 -0.80 -1.20 -2.04 -0.81 0.32
Z score (@ 32 µg/ml)
24-02-2024 Dept. of Pharmaceutical Chemistry 36
Interpretation of results:
 Percentage growth inhibition of an individual sample is calculated based on
Negative controls and Positive Controls .
 Please note Negative inhibition value mean that the growth rate is higher compared
to the Negative Control.
 The growth rates for all bacteria and fungi has a variation of -/+ 10%, which lies in
within expected normal distribution of microbial growth.
 Please note Negative inhibition value means that the growth rate is higher compared
to the Positive Control .
 The growth rates have a variation of -10% or 10%, which is within the reported
normal distribution of bacterial growth.
 Any significant variation is identified by the modified Z-Score, and actives are
selected by a combination of inhibition value and Z-Score.
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Specifications of Earth worms:
 Indian earthworm Pheretima posthuma (Annelida) were collected from the water
logged areas of soil
 Average size of earthworm being 7-10 cm.
 The anthelmintic assay was carried as per the method of Ajayieobaet al.
 The assay was performed on adult Indian earthworm Pheretima posthuma, due to its
anatomical and physiological resemblance with the intestinal roundworm parasites of
human beings.
 Pheretima posthuma worms are easily available and used as a suitable model for
screening of anthelmintic drug
Place of Screening: Drug screening laboratory, Centre for Pharmaceutical Research Unit,
Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapur. (Project
approval ID: RR/2013 -17/UG/11)
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Each petridish was placed with 3 worms and observed for paralysis or
death.
Mean time for paralysis was noted when no movement of any sort could
be observed, except when the worm was shaken vigorously; the time
death of worm (min) was recorded after ascertaining that worms neither
moved when shaken nor when given external stimuli.
The test results were compared with Reference compound Albendazole
(1, 2.5, 10 mg/ml) treated samples.
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Collection of data:-
The time taken for paralysis and death time of worms were
observed and recorded neither after ascertaining that the worms did
not move neither when shaken vigorously nor when dipped in warm
water (50°C).
Statistical Analysis:-
Worm counts were expressed as mean ± SEM. The
significance of difference between the means was determined by
Student’s t-test using a computer software package and considered as
significant when 𝑃<0. 05.
Death
Paralysis
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Compound code 1mg/ml 2.5mg/ml 10mg/ml
Camphor 44.21±4.45* 14:58±1.24* 05:09±0.34*
CSA 60:53±5.33* 22:56±2.22* 12:56±1.12*
ABC-1 60:10±5.24* 10:15±1.56* 02:15±0.16*
ABC-2 15:58±1.45* 10:01±1.23* 05:32±0.44*
ABC-3 18:25±1.26* 13:43±1.28* 10:51±1.31*
ABC-4 17:05±1.44* 15:48±1.46* 06:02±0.54*
ABC-5 29:36±2.33* 14:21±1.32* 12:03±1.18*
ABC-6 56:20±5.36* 48:25±4.48* 09:56±1.02*
ABC-7 24:50±2.35* 22:47±2.22* 13:54±1.13*
XYZ-1 54:26±5.02* 38:58±3.10* 12:55±1.06*
XYZ-2 28:42±2.16* 21:05±2.20* 06:07±0.45*
XYZ-3 20:47±2.12* 18:43±2.32* 10:23±0.56*
XYZ-4 28:43±3.12* 14:23±1.42* 07:09±1.01*
XYZ-5 62:12±7.26* 20:32±1.58* 13:46±1.53*
XYZ-6 56:58±6.36* 42:01±3.13* 13:12±0.54*
XYZ-7 10:50±0.56* 10:49±0.45* 10:52±1.12*
Albendazole 35:32±1.43* 32:48±1.52* 27:23±1.06*
Negative control 160 160 160
Anthelmintic activity against Pheretima posthuma: Mean Paralysis data (in minutes: Seconds (n = 3)
* -p value is less than 0.001 compared to negative control
24-02-2024 Dept. of Pharmaceutical Chemistry 41
0
20
40
60
80
100
120
140
160
Camphor
CSA
ABC-1
ABC-2
ABC-3
ABC-4
ABC-5
ABC-6
ABC-7
XYZ-1
XYZ-2
XYZ-3
XYZ-4
XYZ-5
XYZ-6
XYZ-7
Albendazole
Negative…
1mg/ml
2.5mg/ml
10mg/ml
Anthelmintic activity against Pheretima posthuma: Mean Paralysis data
24-02-2024 Dept. of Pharmaceutical Chemistry 42
Compound code 1mg/ml 2.5mg/ml 10mg/ml
Camphor 44.21±4.45* 14:58±1.24* 05:09±0.34*
CSA 60:53±5.33* 22:56±2.22* 12:56±1.12*
ABC-1 60:10±5.24* 10:15±1.56* 02:15±0.16*
ABC-2 15:58±1.45* 10:01±1.23* 05:32±0.44*
ABC-3 18:25±1.26* 13:43±1.28* 10:51±1.31*
ABC-4 17:05±1.44* 15:48±1.46* 06:02±0.54*
ABC-5 29:36±2.33* 14:21±1.32* 12:03±1.18*
ABC-6 56:20±5.36* 48:25±4.48* 09:56±1.02*
ABC-7 24:50±2.35* 22:47±2.22* 13:54±1.13*
XYZ-1 54:26±5.02* 38:58±3.10* 12:55±1.06*
XYZ-2 28:42±2.16* 21:05±2.20* 06:07±0.45*
XYZ-3 20:47±2.12* 18:43±2.32* 10:23±0.56*
XYZ-4 28:43±3.12* 14:23±1.42* 07:09±1.01*
XYZ-5 62:12±7.26* 20:32±1.58* 13:46±1.53*
XYZ-6 56:58±6.36* 42:01±3.13* 13:12±0.54*
XYZ-7 10:50±0.56* 10:49±0.45* 10:52±1.12*
Albendazole 40:32±1.43* 42:48±1.52* 37:32±1.06*
Negative control 160 160 160
Anthelmintic activity against Pheretima posthuma: Mean death time (in minutes: Seconds (n = 3)
* -p value is less than 0.001 compared to negative control
24-02-2024 Dept. of Pharmaceutical Chemistry 43
0
20
40
60
80
100
120
140
160 Camphor
CSA
ABC-1
ABC-2
ABC-3
ABC-4
ABC-5
ABC-6
ABC-7
XYZ-1
XYZ-2
XYZ-3
XYZ-4
XYZ-5
XYZ-6
XYZ-7
Albendazole
Negative
control
1mg/ml
2.5mg/ml
10mg/ml
Anthelmintic activity against Pheretima posthuma: Mean death data
24-02-2024 Dept. of Pharmaceutical Chemistry 44
The designed schemes utilized camphor and camphor sulfonic acids as
hydrophobic scaffold, and qunoxiline, Isatin, salicylic acid, benzoin,
quinolone were used as pharmacophore. The molecules were obtained
through "Blanc reaction” using conventional synthesis. The purity of the
compounds was tested based on the TLC.
24-02-2024 Dept. of Pharmaceutical Chemistry 45
24-02-2024 Dept. of Pharmaceutical Chemistry 46
R1 R2
Qunoxiline-2-dione -H
BPA -SO3H
BPQSBPQ
SBPQ
BENZOIN
SALICYLIC ACID
ISATIN
Structure activity relationship – Antimicrobial property
O
H2C
R1
R2
24-02-2024 Dept. of Pharmaceutical Chemistry 47
• Camphor derivative of selected pharmacopeia relatively more active when
compare to camphor.
• The active observation is true especially for Isatin derivatives and salicylic acid
derivatives.
• The benzoin derivatives exhibited 10-20% inhibition agonist klebsiella pneumonia
(organism).
• Among all compounds Isatin and salicylic acid derivative are exhibited percentage
inhibition of 63 and 25 respectively agonist drug resistance candida albicans.
• None of the compound is agonist Cryptococcus and also pseudomonas aeruginosa.
• The derivative of qunoxiline is exhibited 20% agonist acinetobacter baumannii.
• All compounds exhibited <10% whereas Isatin derivative lone exhibited 40%
inhibition MRSA and 25% agonist candida albicans.
• Over all salicylic acid derivatives of camphor is documented as practically active
agonist drug resistance candida albicans.
Structure activity relationship – Antimicrobial property
24-02-2024 Dept. of Pharmaceutical Chemistry 48
Structure activity relationship – Anthelmintic property
• SAR was developed based on comparison of camphor and synthesis derivatives the
following observations are made.
• Out of among all camphor sulphonic acid derivatives were found to be inactive
against earthworms
• The benzoin derivatives of camphor is two times more potent than Camphor
sulphonic acid derivatives
• Attachment of qunoxiline 2,3-dione to camphor or camphor sulphonic acid did not
show any improved anthelmintic activity
• Biphenyl qunoxiline derivatives were found to be relatively more potent.
• However camphor sulphonic acid derivatives of camphor decrease the potency to
half the compounds
24-02-2024 Dept. of Pharmaceutical Chemistry 49
• The sulphonyl chloride as well as sulfonamide derivative of qunoxiline with
camphor exhibits equal potency against earthworms.
• Out of all these compounds except Isatin derivatives rest of the compounds exhibit
dose dependent
• The most active compounds of the series are ABC-3 > XYZ-7 > ABC-4 >ABC-2 >
XYZ-3.
• The lipohilicity more than 7 was found to be suitable for anthelmintic activity.
• Isatin lipohilicity is low but it is still potent and show potent activity.
• So that the mechanism of Isatin derivatives will be different from that of qunoxiline
• Overall qunoxiline &Isatin were more active against earthworms salicylic acid
derivatives are drug resistance candida albicans
24-02-2024 Dept. of Pharmaceutical Chemistry 50
The semi-synthetic derivatives of camphor exhibited potent
Anthelmintic activity against earthworm with p value of less than 0.001,
whilst the activity towards virulent pathogens was not satisfactory.
However, salicylic acid bearing camphor compound exhibited
considerable inhibition against drug resistant Candida sp., and rest of
the compounds exhibited below 50% inhibition at a concentration of
35µg/ml.
24-02-2024 Dept. of Pharmaceutical Chemistry 51
24-02-2024 Dept. of Pharmaceutical Chemistry 52
1. Dr Alysha Elliott (+61 7 3346 2745) C/O Dr Paul Lovelock (+61 7 3346
2211) Institute for Molecular Bioscience / QBP Bldg 80, Services Rd The
University of Queensland St Lucia, QLD 4072 AUSTRALIA
2. V. Kishor Kumar1*, P. Satheesh Kumar1 and T.Venkatachalam2
Investigation Of Anthelmintic Activity Of Pergularia Daemia Leaves
Pharmacophore 2014, Vol. 5 (1), 44-48 USA CODEN: PHARM7 ISSN
2229-5402
3. Church, John (1797). An inaugural dissertation on camphor: submitted to
the examination of the Rev. John Ewing, S.S.T.P. provost; the trustees &
medical faculty of the University of Pennsylvania, on the 12th of May,
1797; for the degree of Doctor of Medicine. University of Philadelphia:
Printed by John Thompson. Retrieved January 18, 2013.
4. Green, B. G. (1990). "Sensory characteristics of camphor". The Journal of
Investigative Dermatology. 94 (5): 662–6. doi:10.1111/1523-
1747.ep12876242. PMID 2324522.
24-02-2024 Dept. of Pharmaceutical Chemistry 53
24-02-2024 Dept. of Pharmaceutical Chemistry 54

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New semi-synthetic derivatives of camphor and evaluation for their growth inhibitory potential against drug resistant pathogens and Earthworms

  • 1. New semi-synthetic derivatives of camphor and evaluation for their growth inhibitory potential against drug resistant pathogens and Earthworms Dr. M. Geethavani, M. Pharm., PhD Professor & HOD Department of pharmaceutical Chemistry Balaji college of Pharmacy Ananthapuramu, Andhra Pradesh State, INDIA - 515721 Research work
  • 2. 24-02-2024 Dept. of Pharmaceutical Chemistry 2
  • 3. There are three types of threats have been classified, the classification is appended below, A)Urgent threats: • Drug resistant Clostridium difficile, • Carbapenem-resistant Enterobacteriaceae (CRE), • Drug-resistant Neisseria gonorrhea. B)Serious Threats • Multidrug-resistant tuberculosis (MDR-TB), • drug resistant Acinetobacter, Campylobacter, Pseudomonas, Salmonella, Shigella, • Methicillin-resistant Staphylococcus aureus (MRSA) • Extended spectrum β-lactamase producing Enterobacteriaceae (ESBLs), • Drug-resistant Streptococcus pneumonia, • Fluconazole-resistant Candida. C) Concerning Threats • Vancomycin-resistant Staphylococcus aureus (VRSA), • Erythromycin-resistant Group A streptococcus, • Clindamycin-resistant Group B Streptococcus. 24-02-2024 Dept. of Pharmaceutical Chemistry 3
  • 4. 24-02-2024 Dept. of Pharmaceutical Chemistry 4
  • 5.  Camphor is a waxy, white or transparent solid with a strong aromatic odour which sublimates at room temperature and melts at 180 °C.  It is practically insoluble in water, but soluble in alcohol, ether, chloroform and other organic solvents.  In Asia, a major source of camphor is camphor basil (Ocimum kilimandscharicum).  The East African camphorwood tree (Ocotea usambarensis).  In the 19th century, it was known that nitric acid oxidizes camphor into camphoric acid, this serves as basis for camphor derivatives. 24-02-2024 Dept. of Pharmaceutical Chemistry 5
  • 6.  Used as explosive.  Pest deterrent & preservative.  Used as culinary.  Used as flavouring agent.  Used in cosmetic.  used externally to relieve arthritic and rheumatic pains, neuralgia, and back pain.  It is often used in steam vapourizors to help control coughs by producing a local anesthetic action to the throat and to loosen congestion due to colds. 24-02-2024 Dept. of Pharmaceutical Chemistry 6
  • 7.  The rapid emergences of resistant bacteria jeopardize the efficacy of antibiotics and have turned out as public threat.  The Centers for Disease Control and Prevention (CDC) has categorized the drug resistant pathogens presented as urgent, serious, and concerning threats, which are playing key role in antibiotic crisis and financial burden not only on developing countries like India but also to developed nations like USA.  As per WHO, there should be urgent need of new antibiotics with novel mechanism to save 10 million people death by 2050.  Till today only combination therapy was the priority to manage resistance, but the battle was over.  Hence, this work was designed to explore possible semi-synthetic derivatives of camphor by condensation with various potent pharmacophore such as qunoxiline, Isatin, salicylic acid etc. for antibacterial potential against drug resistant infections and anthelmintic activity. 24-02-2024 Dept. of Pharmaceutical Chemistry 7
  • 8.  To explore possible new semi-synthetic derivatives of camphor through methylene bridge using potent antimicrobial pharmacophore such as salicylic acid, Isatin, benzoin and qunoxiline.  To characterize the structures of new compounds with physical and spectral data.  To evaluate the antimicrobial / growth inhibitory potential of new derivatives against drug resistant species.  To evaluate the anthelmintic activity against earthworms.  To develop a structure activity relationship for their growth inhibitory potential against drug resistant pathogens.  To recommend the future research directions. 24-02-2024 Dept. of Pharmaceutical Chemistry 8
  • 9. Step 2 Step 3 Step 1  Literature survey.  Chemical synthesis and Purification.  Characterization of compounds.  Screening for antimicrobial / anthelmintic potential.  Development of Structure activity relationship.  Make recommendation for further research. 24-02-2024 Dept. of Pharmaceutical Chemistry 9
  • 10. 24-02-2024 Dept. of Pharmaceutical Chemistry 10
  • 11. Then the final product was subjected to purification process Reaction was monitored by TLC The reaction mixture was heated to 700c and stirred for 5-8 hours Qunoxiline 2-dione, salicylic acid, Isatin, benzoin, biphenyl qunoxiline, biphenyl amine in to 250 ml beaker containing 100 ml of 35 % HCl and 35 ml of formaldehyde GENERAL SYNTHESIS PROCEDURE :- A mixture of camphor (0.015 mol) 24-02-2024 Dept. of Pharmaceutical Chemistry 11
  • 12. O N N O N N SO2Cl O N N O O N N O O O + O + O N N SO2NH2 N N SO2NH2 O + O + N N N N SO2Cl REACTIONS OF CHEMICALS WITH CAMPHOR AS GIVEN ABOVE PROCEDURE ABC-1 ABC-2 ABC-3 ABC-4 24-02-2024 Dept. of Pharmaceutical Chemistry 12
  • 16. Compound code Mol. formula Molecular weight Melting point (ᵒc) Rf value % yield Logp ABC-1 C19H20N2O3 324.37 133 0.96 89.6 3.01 ABC-2 C31H31N3O3S 525.55 146 0.89 92.9 7.26 ABC-3 C31H30N2O 446.58 127 0.78 85.8 7.8 ABC-4 C31H29ClN2O4S 545.09 155 0.92 91.0 8.25 ABC-5 C25H28O3 376.49 101 0.71 87.8 5.49 ABC-6 C18H22O4 302.36 126 0.53 85.5 4.16 ABC-7 C19H21NO3 311.37 103 0.82 89.8 3.3 XYZ-1 C19H20N2O6S 404.44 117 0.91 95.5 1.4 XYZ-2 C31H31N3O6S2 605.17 112 0.78 92.1 5.26 XYZ-3 C31S30N2O4S 526.65 124 0.63 94.8 6.19 XYZ-4 C31H29ClN2O6S2 625.15 135 0.73 88.5 6.64 XYZ-5 C26H32O6S 472.59 155 0.94 92.6 4.75 XYZ-6 C19H26O7S 398.47 147 0.85 93.5 4.36 XYZ-7 C19H21NO6S 391.44 138 0.72 90.5 1.69 Physical data of the compounds after synthesis 24-02-2024 Dept. of Pharmaceutical Chemistry 16
  • 17. Compound Code Name ABC-1 6-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1-yl)methyl)quinoxaline-2,3- dione ABC-2 6,7-diphenyl-3-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1- yl)methyl)quinoxaline-2-sulfonamide ABC-3 4-((6,7-diphenylquinoxalin-2-yl)methyl)-1,7,7- trimethylbicyclo[2.2.1]heptan-2-one ABC-4 6,7-diphenyl-3-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1-yl)methyl) quinoxaline-2-sulfonyl chloride ABC-5 4-(3-(1-hydroxy-2-oxo-2-phenylethyl)benzyl)-1,7,7-Trimethylbicyclo [2.2.1]heptan-2-one ABC-6 2-hydroxy-5-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1- yl)methyl)benzoic acid ABC-7 5-((4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-1-yl)methyl)indoline-2,3- dione IUPAC nomenclature of the synthesized compounds 24-02-2024 Dept. of Pharmaceutical Chemistry 17
  • 18. XYZ-1 (4-((2,3-dioxo-2,3-dihydroquinoxalin-6-yl)methyl)-7,7-dimethyl-2- oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid XYZ-2 6,7-diphenyl-3-((4,7,7-trimethyl-3-oxobicyclo quinoxaline-2- sulfonamide)[2.2.1]heptan-1-yl)methanesulfonic acid XYZ-3 (4-((6,7-diphenylquinoxalin-2-yl)methyl)-7,7-dimethyl-2-oxobicyclo[2.2.1] heptan-1-yl)methanesulfonic acid XYZ-4 (4-((3-(chlorosulfonyl)-6,7-diphenylquinoxalin-2-yl)methyl)-7,7-dimethyl- 2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid XYZ-5 4-(3-(1-hydroxy-2-oxo-2-phenylethyl)benzyl)-7,7-dimethyl-2- oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid XYZ-6 2-hydroxy-5-((4,7,7-trimethyl-3-oxobicyclo)methyl)benzoic acid)[2.2.1] heptan-1-yl)methanesulfonic acid XYZ-7 (4-((2,3-dioxoindolin-5-yl)methyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan- 1-yl)methanesulfonic acid IUPAC nomenclature of the synthesized compounds 24-02-2024 Dept. of Pharmaceutical Chemistry 18
  • 19. 24-02-2024 Dept. of Pharmaceutical Chemistry 19
  • 20. Compound code IR (ATR) in cm-1 ABC-1 3418,2883,1867,1794,1681,1648,1540,1423,1078 ABC-2 3388,1678,1648,1541,1509,1455,1205,1097,600 ABC-3 3524,1843,1718,1577,1366,1272,1118,1069,741,701, ABC-4 3612,3564,2819,1793,1627,1143,1049,1021,759,691 ABC-5 3377,2982,1721,1676,1576,1173,1066,1039,971,745,695,672 ABC-6 3648,3616,2865,2590,1721,1660,1437,1281,1122,687,649 ABC-7 3712,2953,1738,1510,1417,1372,1045,749,609 XYZ-1 3403,2942,1650,1635,1520,1039,953,581,581,567 XYZ-2 3673,3211,3009,2940,2328,1698,1951,1698,1288,1175,766,592,563 XYZ-3 3737,3084,2914,2329,1718,1541,1342,1126,759,694,680 XYZ-4 3648,2982,1719,1579,1366,1273,1119,1070,1014,741,693 XYZ-5 3378,2590,1718,1674,1577,1446,1273,1173,1066,744 XYZ-6 3648,3616,2865,2590,1721,1660,1437,1281,1122,687,649 XYZ-7 3311,3049,1729,1612,1326,1464,1148,1095,737,574 IR (ATR, Cm-1) spectral data of synthesized compounds 3500 (-OH), 3200 (NH), 3000 (CH), 1700 (C=O), 1600 (C=C) 24-02-2024 Dept. of Pharmaceutical Chemistry 20
  • 21. 24-02-2024 Dept. of Pharmaceutical Chemistry 21 IR Spectra of camphor
  • 22. 24-02-2024 Dept. of Pharmaceutical Chemistry 22 IR Spectra of camphor sulphonic acid
  • 23. 24-02-2024 Dept. of Pharmaceutical Chemistry 23 IR Spectra of benzoin with camphor
  • 24. Chemical shift value in ppm Protons (type) 3.1 – 3.7 cpx, camphor, 4.3 (-CH2-) methylene bridge 6.9-7.9 (aryl H) Aromatic phenyl protons 10.3 9-(OH). Phenolic hydroxyl >12 (COOH) Carboxylic acid group Chemical shift value in ppm Protons (type) 2.3 – 3.9 cpx, camphor, 4.6 (-CH2-) methylene bridge 7.2-8.2 (aryl H) Aromatic phenyl protons >11 (OH) Sulphonic acid group H1NMR spectral data of XYZ-5 (Benzoin Derivatives of camphor sulphonic acid): H1NMR spectra for ABC 6 (salicylic acid Derivatives of camphor): 24-02-2024 Dept. of Pharmaceutical Chemistry 24
  • 25. 24-02-2024 Dept. of Pharmaceutical Chemistry 25 H1NMR spectra for ABC 6 (salicylic acid Derivatives of camphor)
  • 26. 24-02-2024 Dept. of Pharmaceutical Chemistry 26 H1NMR spectral data of XYZ-5 (Benzoin Derivatives of camphor sulphonic acid)
  • 27. Compound code Mol. Formula Molecular weight Mass e/z value ABC-1 C19H20N2O3 324.37 325 (M+H) ABC-2 C31H31N3OS 525.55 327 (M+H) ABC-3 C31H30N2O 446.58 445 (M-H) ABC-4 C31H29CLN2O4S 545.09 546 (M+H) ABC-5 C25H28O3 376.49 377 (M+H) ABC-6 C18H22O4 302.36 320 (M+18) ABC-7 C19H21NO3 311.37 313(M+H) XYZ-1 C19H20N2O6S 404.44 427 (M+23) XYZ-2 C31H31N3O6S2 605.17 628 (M+23) XYZ-3 C31S30N2O4S 526.65 527 (M+H) XYZ-4 C31H29CLN2O6S2 625.15 624 (M-H) XYZ-5 C26H32O6S 471.59 469 (M-H) XYZ-6 C19H26O7S 398.47 400 (M+H) XYZ-7 C19H21NO6S 391.44 390 (M-H) Mass (ESI) Spectral studies (ESI – Positive & Negative mode) 24-02-2024 Dept. of Pharmaceutical Chemistry 27
  • 28. 24-02-2024 Dept. of Pharmaceutical Chemistry 28
  • 29. 24-02-2024 Dept. of Pharmaceutical Chemistry 29
  • 30. 24-02-2024 Dept. of Pharmaceutical Chemistry 30
  • 31. Name Description Strain Organism Type Staphylococcus aureus MRSA ATCC 43300 Bacteria G+ve Escherichia coli FDA control ATCC 25922 Bacteria G-ve Klebsiellapneumoniae MDR ATCC 700603 Bacteria G-ve Acinetobacter baumannii Type strain ATCC 19606 Bacteria G-ve Pseudomonas aeruginosa Type strain ATCC 27853 Bacteria G-ve Candida albicans CLSI reference ATCC 90028 Fungi Yeast Cryptococcus neoformans var. grubii Type strain H99; ATCC 208821 Fungi Yeast Microorganisms used in the study CLSI : Clinical and laboratory standard institute MDR : Multiple drugs resistant MRSA : methicillin resistant Staphylococcus aureus FDA : Food and drug administration Place of Screening: Data Provided by CO-ADD Community for Open Antimicrobial Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, 4072 St Lucia QLD Australia (Project ID: PO319) 24-02-2024 Dept. of Pharmaceutical Chemistry 31
  • 32.  Antibacterial data Collection Inhibition of bacterial growth was determined measuring absorbance at 600 nm (OD600), using a Tecan M1000 Pro monochromator plate reader.  Growth inhibition of C. albicans was determined measuring absorbance at 530 nm (OD530), while the growth inhibition of C. neoformanswas determined measuring the difference in absorbance between 600 and 570 nm (OD600-570), after the addition of reassuring (0.001% final concentration) and incubation at 35 °C for additional 2h. A - [Active] Samples with inhibition values equal to or above 80% and abs (Z-Score) above 2.5 for either replicate (n=2 on different plates) were classed as actives. P - [Partial Active] compounds with inhibition values between 50.9% - 79.9% or abs (Z- Sore) below 2.5. I - Inactive compounds with inhibition values below 50% or abs (Z-Sore) below 2.5. Quality control measures in the study 24-02-2024 Dept. of Pharmaceutical Chemistry 32
  • 33. Compound Code Sa Hit Ec Hit Kp Hit Pa Hit Ab Hit Ca Hit Cn Hit ABC1 I I I I I I I ABC2 I I I I I I I ABC3 I I I I I I I ABC4 I I I I I I I ABC5 I I I I I I I ABC6 I I I I I P I ABC7 I I I I I I I XYZ1 I I I I I I I XYZ2 I I I I I I I XYZ3 I I I I I I I XYZ4 I I I I I I I XYZ5 I I I I I I I XYZ6 I I I I I I I XYZ7 I I I I I I I Summary of the antimicrobial activity (@ 32 µg/ml) 24-02-2024 Dept. of Pharmaceutical Chemistry 33
  • 34. Compound Code Sa Hit Ec Hit Kp Hit Pa Hit Ab Hit Ca Hit Cn Hit ABC1 -0.93 -7.73 -0.07 2.95 7.96 4.39 -20.65 ABC2 3.53 1.17 -1.62 6.03 15.80 4.78 -9.63 ABC3 7.26 6.15 10.13 2.01 25.94 9.59 -26.16 ABC4 2.89 5.96 6.80 -7.33 14.33 6.64 -114.97 ABC5 0.12 9.82 10.79 -5.93 17.29 10.10 -103.27 ABC6 -2.89 0.70 8.00 -16.15 8.11 63.29 -97.41 ABC7 39.44 3.87 12.47 9.57 16.92 24.35 -151.11 XYZ1 3.23 4.32 1.59 2.78 7.01 13.50 -28.22 XYZ2 0.93 8.09 9.27 1.23 8.87 7.98 -90.18 XYZ3 2.45 8.03 8.50 -3.61 5.72 6.32 -87.09 XYZ4 7.13 8.38 12.37 0.40 0.28 4.90 -110.15 XYZ5 0.63 3.83 20.09 -1.60 15.06 7.41 -59.20 XYZ6 5.44 0.10 4.13 0.90 11.41 3.94 -11.01 XYZ7 13.71 1.41 9.81 2.58 24.69 7.41 -61.61 % Inhibition data on drug resistant pathogens (@ 32 µg/ml) 24-02-2024 Dept. of Pharmaceutical Chemistry 34
  • 35. 0 10 20 30 40 50 60 70 ABC1 ABC2 ABC3 ABC4 ABC5 ABC6 ABC7 XYZ1 XYZ2 XYZ3 XYZ4 XYZ5 XYZ6 XYZ7 Sa Hit Ec Hit Kp Hit Pa Hit Ab Hit Ca Hit Cn Hit % Inhibition data on drug resistant pathogens (@ 32 µg/ml) 24-02-2024 Dept. of Pharmaceutical Chemistry 35
  • 36. Compound Code Sa Hit Ec Hit Kp Hit Pa Hit Ab Hit Ca Hit Cn Hit ABC1 -0.24 0.99 0.60 -1.30 -0.01 0.26 -0.58 ABC2 -0.82 -0.36 0.82 -2.06 -0.96 0.12 -0.83 ABC3 -1.30 -1.12 -0.85 -1.06 -2.19 -1.58 -0.46 ABC4 -0.74 -1.09 -0.37 1.24 -0.78 -0.53 1.50 ABC5 -0.38 -1.68 -0.94 0.90 -1.14 -1.77 1.24 ABC6 0.00 -0.29 -0.55 3.43 -0.03 -20.72 1.11 ABC7 -5.42 -0.77 -1.18 -2.94 -1.10 -6.84 2.30 XYZ1 -0.78 -0.84 0.36 -1.25 0.09 -2.98 -0.41 XYZ2 -0.48 -1.42 -0.73 -0.87 -0.12 -1.01 0.95 XYZ3 -0.68 -1.41 -0.62 0.32 0.25 -0.42 0.88 XYZ4 -1.28 -1.46 -1.17 -0.66 0.90 0.08 1.39 XYZ5 -0.45 -0.77 -2.27 -0.17 -0.87 -0.81 0.26 XYZ6 -1.06 -0.20 0.00 -0.79 -0.43 0.42 -0.80 XYZ7 -2.12 -0.40 -0.80 -1.20 -2.04 -0.81 0.32 Z score (@ 32 µg/ml) 24-02-2024 Dept. of Pharmaceutical Chemistry 36
  • 37. Interpretation of results:  Percentage growth inhibition of an individual sample is calculated based on Negative controls and Positive Controls .  Please note Negative inhibition value mean that the growth rate is higher compared to the Negative Control.  The growth rates for all bacteria and fungi has a variation of -/+ 10%, which lies in within expected normal distribution of microbial growth.  Please note Negative inhibition value means that the growth rate is higher compared to the Positive Control .  The growth rates have a variation of -10% or 10%, which is within the reported normal distribution of bacterial growth.  Any significant variation is identified by the modified Z-Score, and actives are selected by a combination of inhibition value and Z-Score. 24-02-2024 Dept. of Pharmaceutical Chemistry 37
  • 38. Specifications of Earth worms:  Indian earthworm Pheretima posthuma (Annelida) were collected from the water logged areas of soil  Average size of earthworm being 7-10 cm.  The anthelmintic assay was carried as per the method of Ajayieobaet al.  The assay was performed on adult Indian earthworm Pheretima posthuma, due to its anatomical and physiological resemblance with the intestinal roundworm parasites of human beings.  Pheretima posthuma worms are easily available and used as a suitable model for screening of anthelmintic drug Place of Screening: Drug screening laboratory, Centre for Pharmaceutical Research Unit, Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapur. (Project approval ID: RR/2013 -17/UG/11) 24-02-2024 Dept. of Pharmaceutical Chemistry 38
  • 39. Each petridish was placed with 3 worms and observed for paralysis or death. Mean time for paralysis was noted when no movement of any sort could be observed, except when the worm was shaken vigorously; the time death of worm (min) was recorded after ascertaining that worms neither moved when shaken nor when given external stimuli. The test results were compared with Reference compound Albendazole (1, 2.5, 10 mg/ml) treated samples. 24-02-2024 Dept. of Pharmaceutical Chemistry 39
  • 40. Collection of data:- The time taken for paralysis and death time of worms were observed and recorded neither after ascertaining that the worms did not move neither when shaken vigorously nor when dipped in warm water (50°C). Statistical Analysis:- Worm counts were expressed as mean ± SEM. The significance of difference between the means was determined by Student’s t-test using a computer software package and considered as significant when 𝑃<0. 05. Death Paralysis 24-02-2024 Dept. of Pharmaceutical Chemistry 40
  • 41. Compound code 1mg/ml 2.5mg/ml 10mg/ml Camphor 44.21±4.45* 14:58±1.24* 05:09±0.34* CSA 60:53±5.33* 22:56±2.22* 12:56±1.12* ABC-1 60:10±5.24* 10:15±1.56* 02:15±0.16* ABC-2 15:58±1.45* 10:01±1.23* 05:32±0.44* ABC-3 18:25±1.26* 13:43±1.28* 10:51±1.31* ABC-4 17:05±1.44* 15:48±1.46* 06:02±0.54* ABC-5 29:36±2.33* 14:21±1.32* 12:03±1.18* ABC-6 56:20±5.36* 48:25±4.48* 09:56±1.02* ABC-7 24:50±2.35* 22:47±2.22* 13:54±1.13* XYZ-1 54:26±5.02* 38:58±3.10* 12:55±1.06* XYZ-2 28:42±2.16* 21:05±2.20* 06:07±0.45* XYZ-3 20:47±2.12* 18:43±2.32* 10:23±0.56* XYZ-4 28:43±3.12* 14:23±1.42* 07:09±1.01* XYZ-5 62:12±7.26* 20:32±1.58* 13:46±1.53* XYZ-6 56:58±6.36* 42:01±3.13* 13:12±0.54* XYZ-7 10:50±0.56* 10:49±0.45* 10:52±1.12* Albendazole 35:32±1.43* 32:48±1.52* 27:23±1.06* Negative control 160 160 160 Anthelmintic activity against Pheretima posthuma: Mean Paralysis data (in minutes: Seconds (n = 3) * -p value is less than 0.001 compared to negative control 24-02-2024 Dept. of Pharmaceutical Chemistry 41
  • 43. Compound code 1mg/ml 2.5mg/ml 10mg/ml Camphor 44.21±4.45* 14:58±1.24* 05:09±0.34* CSA 60:53±5.33* 22:56±2.22* 12:56±1.12* ABC-1 60:10±5.24* 10:15±1.56* 02:15±0.16* ABC-2 15:58±1.45* 10:01±1.23* 05:32±0.44* ABC-3 18:25±1.26* 13:43±1.28* 10:51±1.31* ABC-4 17:05±1.44* 15:48±1.46* 06:02±0.54* ABC-5 29:36±2.33* 14:21±1.32* 12:03±1.18* ABC-6 56:20±5.36* 48:25±4.48* 09:56±1.02* ABC-7 24:50±2.35* 22:47±2.22* 13:54±1.13* XYZ-1 54:26±5.02* 38:58±3.10* 12:55±1.06* XYZ-2 28:42±2.16* 21:05±2.20* 06:07±0.45* XYZ-3 20:47±2.12* 18:43±2.32* 10:23±0.56* XYZ-4 28:43±3.12* 14:23±1.42* 07:09±1.01* XYZ-5 62:12±7.26* 20:32±1.58* 13:46±1.53* XYZ-6 56:58±6.36* 42:01±3.13* 13:12±0.54* XYZ-7 10:50±0.56* 10:49±0.45* 10:52±1.12* Albendazole 40:32±1.43* 42:48±1.52* 37:32±1.06* Negative control 160 160 160 Anthelmintic activity against Pheretima posthuma: Mean death time (in minutes: Seconds (n = 3) * -p value is less than 0.001 compared to negative control 24-02-2024 Dept. of Pharmaceutical Chemistry 43
  • 45. The designed schemes utilized camphor and camphor sulfonic acids as hydrophobic scaffold, and qunoxiline, Isatin, salicylic acid, benzoin, quinolone were used as pharmacophore. The molecules were obtained through "Blanc reaction” using conventional synthesis. The purity of the compounds was tested based on the TLC. 24-02-2024 Dept. of Pharmaceutical Chemistry 45
  • 46. 24-02-2024 Dept. of Pharmaceutical Chemistry 46
  • 47. R1 R2 Qunoxiline-2-dione -H BPA -SO3H BPQSBPQ SBPQ BENZOIN SALICYLIC ACID ISATIN Structure activity relationship – Antimicrobial property O H2C R1 R2 24-02-2024 Dept. of Pharmaceutical Chemistry 47
  • 48. • Camphor derivative of selected pharmacopeia relatively more active when compare to camphor. • The active observation is true especially for Isatin derivatives and salicylic acid derivatives. • The benzoin derivatives exhibited 10-20% inhibition agonist klebsiella pneumonia (organism). • Among all compounds Isatin and salicylic acid derivative are exhibited percentage inhibition of 63 and 25 respectively agonist drug resistance candida albicans. • None of the compound is agonist Cryptococcus and also pseudomonas aeruginosa. • The derivative of qunoxiline is exhibited 20% agonist acinetobacter baumannii. • All compounds exhibited <10% whereas Isatin derivative lone exhibited 40% inhibition MRSA and 25% agonist candida albicans. • Over all salicylic acid derivatives of camphor is documented as practically active agonist drug resistance candida albicans. Structure activity relationship – Antimicrobial property 24-02-2024 Dept. of Pharmaceutical Chemistry 48
  • 49. Structure activity relationship – Anthelmintic property • SAR was developed based on comparison of camphor and synthesis derivatives the following observations are made. • Out of among all camphor sulphonic acid derivatives were found to be inactive against earthworms • The benzoin derivatives of camphor is two times more potent than Camphor sulphonic acid derivatives • Attachment of qunoxiline 2,3-dione to camphor or camphor sulphonic acid did not show any improved anthelmintic activity • Biphenyl qunoxiline derivatives were found to be relatively more potent. • However camphor sulphonic acid derivatives of camphor decrease the potency to half the compounds 24-02-2024 Dept. of Pharmaceutical Chemistry 49
  • 50. • The sulphonyl chloride as well as sulfonamide derivative of qunoxiline with camphor exhibits equal potency against earthworms. • Out of all these compounds except Isatin derivatives rest of the compounds exhibit dose dependent • The most active compounds of the series are ABC-3 > XYZ-7 > ABC-4 >ABC-2 > XYZ-3. • The lipohilicity more than 7 was found to be suitable for anthelmintic activity. • Isatin lipohilicity is low but it is still potent and show potent activity. • So that the mechanism of Isatin derivatives will be different from that of qunoxiline • Overall qunoxiline &Isatin were more active against earthworms salicylic acid derivatives are drug resistance candida albicans 24-02-2024 Dept. of Pharmaceutical Chemistry 50
  • 51. The semi-synthetic derivatives of camphor exhibited potent Anthelmintic activity against earthworm with p value of less than 0.001, whilst the activity towards virulent pathogens was not satisfactory. However, salicylic acid bearing camphor compound exhibited considerable inhibition against drug resistant Candida sp., and rest of the compounds exhibited below 50% inhibition at a concentration of 35µg/ml. 24-02-2024 Dept. of Pharmaceutical Chemistry 51
  • 52. 24-02-2024 Dept. of Pharmaceutical Chemistry 52 1. Dr Alysha Elliott (+61 7 3346 2745) C/O Dr Paul Lovelock (+61 7 3346 2211) Institute for Molecular Bioscience / QBP Bldg 80, Services Rd The University of Queensland St Lucia, QLD 4072 AUSTRALIA 2. V. Kishor Kumar1*, P. Satheesh Kumar1 and T.Venkatachalam2 Investigation Of Anthelmintic Activity Of Pergularia Daemia Leaves Pharmacophore 2014, Vol. 5 (1), 44-48 USA CODEN: PHARM7 ISSN 2229-5402 3. Church, John (1797). An inaugural dissertation on camphor: submitted to the examination of the Rev. John Ewing, S.S.T.P. provost; the trustees & medical faculty of the University of Pennsylvania, on the 12th of May, 1797; for the degree of Doctor of Medicine. University of Philadelphia: Printed by John Thompson. Retrieved January 18, 2013. 4. Green, B. G. (1990). "Sensory characteristics of camphor". The Journal of Investigative Dermatology. 94 (5): 662–6. doi:10.1111/1523- 1747.ep12876242. PMID 2324522.
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  • 54. 24-02-2024 Dept. of Pharmaceutical Chemistry 54