on pharma chemistry

1. COMPUTATIONAL STUDY AND SYNTHESIS OF THE
THERAPEUTIC POTENTIALS OF A NOVEL
ACENAPHTHAQUINONE-IMIDAZOLE HYBRIDS
Presented By
G.LAKSHMI
M. Pharmacy II year, OUCT
GUIDED BY
Dr. ANITHA SADHULA,
Asst. Professor (C), OUCT
NATIONAL CONFERENCE ON “TRENDING RESEARCH &
INNOVATIONS IN PHARMACEUTICAL SCIENCES (TRIPS-2022)
ORAL PRESNETATION ON

2. CONTENTS
Introduction
Aim and Objective
Synthesis, Docking studies and ADMET properties
prediction
Results
Conclusion
References

3. INTRODUCTION
ACENAPHTHOQUINONE
Acenapthoquinone is a quinone derived from acenaphthene.
Insoluble in water and soluble in alcohol.
Uses :
It is used as an intermediate for the manufacturing of dyes, and
pharmaceuticals.
Acenaphthene derivatives have gained great importance due to
their diverse biological properties including antitumor, antifungal,
antimicrobial, anti-inflammatory, and insecticidal activities.

4. IMIDAZOLES:
• Imidazole is an organic aromatic heterocycle
compound, classified as a diazole, and has non-adjacent
nitrogen atoms. It is amphoteric in nature.
Uses:
• Anti-carcinogen
• Antimicrobial
• Anti-ulcer agent
• Anti-convulsant
• Anti-allergic
• Anti-inflammatory
• Analgesic
• Anxiolytic
• Anti-diabetic
• Antimalarial
• Cyclin-dependent kinase inhibitors

5. Scheme
O
O
+ + 2 NH4OAc
Ammonium acetate
Glacial acetic acid
acenaphthylene-1,2-dione
(1)
Aryl aldehyde
(3)
Zeolite
(2a-2j)
Ar-CHO
N
H
N
Ar
MW (450W)
ANQ imidazole derivative
(4a-4j)

6. Compound Melting point (0C) % Yield
4a 148-150 0C 71.4
4b 180-1850C 80
4c 1900C 75
4d 130-1350C 76.4
4e 145-1530C 81.2
4f 170-1750C 81.2
4g 1450C 55.5
4h 150-1520C 77.7
4i 138-1400C 75
4j 1500C 80
Physical data of the synthesized compounds

7. Mass spectra of the unsubstitued compound
M.F. C19H12N2 (M+1)+

8. 1H NMR spectra of unsubstituted compound

9. 13C NMR spectra of unsubstituted compound

10. Compounds Binding score (kcal/mol)
PEROXIREDOXINS
(PDB ID: 3MNG):
INHA (PDB ID:
5G0W) :
4a -6.5 -10.1
4b -6.6 -10.3
4c -6.7 -10.4
4d -6.8 -11.2
4e -6.8 -11.2
4f -6.4 -10.5
4g -6.5 -10.5
4h -6.2 -10.1
4i -6.3 -10.9
4j -6.3 -10.7
Ascorbic acid -4.4 -5.8 (isoniazid)
Results: Molecular docking scores of ligands against targets

11. Compounds
Binding score (kcal/mol)
HIF-1(PDB
ID: 1H2M):
MAP kinase
(PDB ID:
1S9I) :
Hsp90 (PDB
ID:5XQE) :
topoisomerase IIA
(PDB ID: 1ZXN):
4a -8 -9.2 -10.8 -9.3
4b -8.5 -9.5 -9.6 -10
4c -8.1 -9.6 -10.9 -10.1
4d -8.6 -9.8 -10.6 -10.6
4e -8.8 -10 -10 -10.3
4f -8.2 -10 -9.5 -9.9
4g -8.3 -9.5 -9.3 -9.7
4h -8.1 -9.4 -10 -9.4
4i -8.6 -9.7 -9.6 -10.2
4j -8.2 -9.7 -9.4 -10.1
Doxorubicin -5.4 -9.0 -9.1 -6.9

12. Compounds Binding score (kcal/mol)
FPPS (PDB ID:
1rqi):
Topo I (PDB ID:
1x75) :
DNA gyrase
(PDB ID:3nuh):
4a -9.1 -7.6 -8.1
4b -9.4 -7.6 -7.3
4c -9.1 -7.7 -8.1
4d -9.6 -7.9 -8.3
4e -9.9 -8.6 -7.7
4f -8.8 -7.7 -7.1
4g -9 -7.8 -7.5
4h -8.8 -6.8 -7.3
4i -9.2 -7.1 -7.7
4j -9.1 -7.5 -7.4
Ciprofloxacin -8.9 -5.5 -6.5

13. Figure 1: Indicates binding interactions of compound 4d with INHA :
Figure 2 : Indicates binding interactions of compound isoniazid with INHA :

14. Figure 3: Indicates binding interactions of compound 4cwith HSP90 :
Figure 4 : Indicates binding interactions of doxorubicin with HSP90 :

15. Compounds
Molecular
formula
Molecular
weight
Number of
hydrogen
bond
acceptors
Number
of
rotatable
bonds
Number of
hydrogen
donors
TPSA(Å2)
LogP(cLogP)
Lipinski’s
rule of five
4a C19H12N2 268.31 1 1 1 28.68 2.38 0
4b C19H12N2O 284.31 2 2 1 48.91 2.1 0
4c C20H14N2O 298.34 2 1 2 37.91 2.77 0
4d C19H11N3O2 313.31 3 1 2 74.5 2.09 0
4e C21H13N3 307.35 1 1 2 44.47 2.23 0
4f C19H10Cl2N
2 302.76
1 1 1 28.68
2.64 1
4g C19H11ClN2 337.2 1 2 1 28.68 2.67 1
4h C21H16N2O2 328.36 3 1 3 47.14 2.76 0
4i C20H11N3 293.32 2 1 1 52.47 2.29 0
4j C22H18N2 310.39 1 1 2 28.68 2.99 1
Doxorubicin C27H29NO11 543.52 12 6 5 206.07 2.16 3
Ciprofloxaci
n
C17H18FN3
O3 331.34
5 3 2 74.57
2.24 0
Ascorbic
acid C6H8O6 176.12
6 2 4 107.22
0.59 0
Isoniazid C6H7N3O 137.14 3 2 3 68.01 0.03 0
Leadlikeness prediction of compounds via SwissADME :

16. Compounds
Gastroi
ntestin
al
absorpt
ion
Blood
brain
barrier
perme
ability
Pgp
substra
te
CYP4a2
inhibitor
CYP
2C19
inhib
itor
CYP2C
9
inhibitor
CYP2D
6
inhibito
r
CYP3A
4
inhibito
r
Skin
permeability
log Kp (cm/s)
4a
High
Yes
Yes Yes No No Yes Yes
-4.83
4b High Yes Yes Yes Yes No Yes Yes -5.18
4c
High
Yes Yes Yes Yes No Yes Yes -5.03
4d
High
No Yes Yes Yes No Yes No -5.23
4e
High
Yes Yes Yes No No Yes No -4.98
4f High Yes Yes Yes Yes No No Yes -4.6
4g
High
No Yes Yes Yes No No Yes -4.36
ADME properties of compounds via SwissADME

17. 4h
High
Yes Yes Yes Yes No Yes Yes -5.24
4i
High
Yes Yes Yes Yes No Yes Yes -5.19
4j
High
No Yes Yes Yes No Yes Yes -4.29
Doxorubicin
No Yes No No No No No -8.71
Ciprofloxacin
High
No Yes No No No No No -9.09
Ascorbic acid
High
No No No No No No No -8.54
Isoniazid
High
No No No No No No No -7.63

18. Compoun
ds
LD50
(mg/kg)
Toxicit
y
class
Hepatotoxicit
y
Carcinogenicity Immunotoxicit
y
Mutage
nicity
Cytotoxicit
y
4a 300 3 Active Inactive Inactive Active Inactive
4b 300 3 Active Inactive Inactive Active Inactive
4c 2000 4 Active Inactive Active Active Inactive
4d 300 3 Active Active Active Active Inactive
4e 300 3 Active Inactive Active Active Inactive
4f 300 3 Active Inactive Active Inactive Inactive
4g 300 3 Inactive Inactive Active Inactive Inactive
4h 2000 4 Active Inactive Active Inactive Inactive
4i 300 3 Active Inactive Inactive Active Inactive
4j 300 3 Inactive Inactive Active Active Inactive
Doxorubi
cin
205 3 Inactive Inactive Active Active Active
Ciproflox
acin
2000 4 Inactive Inactive Inactive Active Inactive
Ascorbic
acid
3367 5 Inactive Inactive Inactive Inactive Inactive
Isoniazid 133 3 Active Active Inactive Inactive Inactive
Toxicity analysis of compounds by ProTox II

19. compound Intra peritoneal route of
administration
Intravenous route of
administration
Oral route of
administration
Subcutaneous route of
administration
LD50
(mg/kg)
Classificati
on of the
substance
toxicity
LD50
(mg/kg)
Classificati
on of the
substance
toxicity
LD50
(mg/kg)
Classificati
on of the
substance
toxicity
LD50
(mg/kg)
Classificati
on of the
substance
toxicity
4a 532.700 Class 5 81.170 Class 4 2120.000 Class 5 455.500 Class 4
4b 492.400 Class 4 80.550 Class 4 1042.000 Class 4 1413.000 Class 5
4c 541.800 Class 5 106.700 Class 4 2565.000 Class 5 1070.000 Class 5
4d 544.900 Class 5 105.300 Class 4 356.100 Class 4 382.600 Class 4
4e 649.100 Class 5 87.730 Class 4 1020.000 Class 4 801.500 Class 4
4f 745.400 Class 5 80.490 Class 4 396.200 Class 4 1135.000 Class 5
4g 726.600 Class 5 77.070 Class 4 628.900 Class 4 2455.000 Class 5
4h 494.700 Class 4 116.300 Class 4 1495.000 Class 4 1273.000 Class 5
4i 663.300 Class 5 76.350 Class 4 289.900 Class 3 460.000 Class 4
4j 495.500 Class 4 91.840 Class 4 852.400 Class 4 632.800 Class 4
doxorubicin 6.389 Class 2 27.810 Class 3 110.800 Class 3
27.750
Class 3
Ascorbic
acid
217.400
Class 4
422.800
Class 5 6707.000 Non Toxic 4226.000 Non Toxic
Ciprofloxac
in
687.000 Class 5 207.700 Class 4
1111.000
Class 4
1206.000
Class 5
Isoniazid 309.600 Class 4 256.100 Class 4 899.700 Class 4
290.200
Class 4
Predicted rat acute toxicity of synthesized compounds GUSAR

20. Compounds
Activities prediction values
Bioaccumulation
factor
Log10(BCF)
Daphnia magna
LC50 -
Log10(mol/L)
Fathead Minnow
LC50
Log10(mmol/L)
Tetrahymena
pyriformis IGC50
Log10(mol/L)
4a 2.239 In AD 5.745 In AD -2.670 In AD 2.121 In AD
4b 1.249 In AD 6.013 In AD -2.721 In AD 2.125 In AD
4c 1.815 In AD 6.461 In AD -2.98 In AD 2.099 In AD
4d 1.701 In AD 6.112 In AD -3.102 In AD 2.305 In AD
4e 1.748 In AD 6.173 In AD -3.224 In AD 2.232 In AD
4f 2.415 In AD 5.996 In AD -3.131 In AD 2.465 In AD
4g 2.663 In AD 6.274 In AD -3.590 In AD 2.676 In AD
4h 1.494 In AD 6.680 In AD -3.075 In AD 2.058 In AD
4i 1.504 In AD 6.279 In AD -2.627 In AD 2.240 In AD
4j 1.494 In AD 6.680 In AD -3.075 In AD 2.058 In AD
doxorubicin
-0.028 In AD 6.390 In AD -3.681 In AD 1.040 In AD
Ascorbic acid 0.373 In AD 3.064 In AD 0.347 In AD -0.965 In AD
Ciprofloxacin 0.023 In AD 4.871 In AD -1.225 In AD 1.060 In AD
Isoniazid
0.350 In AD 3.869 In AD 0.062 In AD -0.190 In AD
Prediction of environmental toxicity by GUSAR:

21. CONCLUSION :
overall 10 novel acenaphthoquinone- imidazole hybrids
were synthesized and purified and structures were
confirmed.
Among all the compounds 4d (-11.2 kcal/mol) and 4c (-
10.9 kcal/mol) having best binding affinity against
respective targets, all the compounds showed minimum
toxicities, better pharmacokinetic profile and drug-
likeness.
These compounds may act as leads for synthesis of
novel

22. REFERENCES :
• Tatsugi, J., Okumura, S., & Izawa, Y. (1986). A Convenient One-Pot
Synthesis of Acenaphthenequinones from 1-Acenaphthenones by NBS–
DMSO Oxidation. Bulletin of the Chemical Society of Japan, 59(10), 3311–
3313. https://doi.org/10.1246/bcsj.59.3311
• Nilesh, S. P., Rutuja, D., Bankar, A. S., Bramhankar, R. V., & Nirmal
Ashwini , A. J. (2022). Rational approaches for synthesis of some novel
imidazole heterocycles with their broad spectrum of pharmacological
activities: a brief review. IJPSR, 13(3),1079-1085.
• Baptista, R., Bhowmick, S., Shen, J., & Mur, L. A. J. (2021). Molecular
Docking Suggests the Targets of Anti-Mycobacterial Natural Products.
Molecules, 26(2), 475. https://doi.org/10.3390/molecules26020475
• Lee, M. M. L., Chan, B. D., Wong, W. Y., Leung, T. W., Qu, Z., Huang, J.,
Zhu, L., Lee, C. S., Chen, S., & Tai, W. C. S. (2020). Synthesis and
Evaluation of Novel Anticancer Compounds Derived from the Natural
Product Brevilin A. ACS Omega, 5(24), 14586–14596.
https://doi.org/10.1021/acsomega.0c01276