Pyrazolopyridine Derivatives As Antileishmanial Agent

1. Prepared by-
VIKRAM SINHA
I.D. NO. 438/MS-MC/17
M.S.(PHARM.)
DEPARTMENT OF MEDICINAL CHEMISTRY
SEMESTER-1ST
120-Jan-18

2. What is Leishmaniasis ?
• Leishmaniasis is a parasitic disease caused by
the Leishmania parasite.
• This parasite typically lives in infected sand
flies.
• Leishmaniasis spread from a bite of an
infected sand fly (Tse-tse fly) belongs to genus
Phlebotomus.
• Designated as a Neglected tropical disease.
220-Jan-18
Nagle, A. S, et al., Chem. Rev., 2014, 114, 11305–11347.

3. Signs And Symptoms
• Pyrexia
• Liver enlargement
• Changes in bone marrow
• Skin lesions
• Anaemia
• Changes in lymph nodes
• Changes in intestine
320-Jan-18
http://www.who.int/leishmaniasis/en/ accessed on 21/11/2017

4. Types of Leishmania
• Cutaneous leishmaniasis: It produces by Leishmania tropica
which is characterized by skin lesion.
• Mucocutaneous leishmania: It produces
by Leishmania braziliensis characterized
by lesion near mucosal membranes.
• Visceral leishmania: It produces by Leishmania Donovani.
Symptoms include fever, enlargement of spleen and
liver,weakness and progressive emaciation.
420-Jan-18
http://www.who.int/leishmaniasis/en/ accessed on 21/11/2017

5. Geographical Distribution of
Leishmaniasis
• An estimated 400,000 new cases of VL occurs
each year all over the world.
• The VL is mainly caused by L.donovani in the
Indian subcontinent and East Africa.
• Unfortunately, 90% of VL patients are present
in six countries,viz.,Bangladesh,Brazil,Ethiopia,
India, South Sudan and Sudan.
520-Jan-18
http://www.who.int/mediacentre/factsheets/fs375/en / accessed on 21/11/2017

6. Lifecycle Of Leishmanial Parasite
620-Jan-18
https://www.cdc.gov/parasites/leishmaniasis/biology.html / accessed on 21/11/2017

7. Prevention And Control
720-Jan-18
https://www.slideshare.net/PakRose1/leishmania-31612660 / accessed on 21/11/2017

8. Efforts of WHO
•On 3,August, 2017, First free Online course was started on
leishmania for prevention of disease and Medication.
•On 26,June, 2017,The WHO had dispatched medical supplies to
Kenya in response to an outbreak Of visceral leishmaniasis in
Marsabit country
with a population
Of over 290000.
820-Jan-18
http://www.who.int/leishmaniasis/en/ / accessed on 21/11/2017

9. Antileishmanial Drugs
• First Line drug
Sodium Stibogluconate
• Second Line drugs
Amphotericin-B
Miltefosine
920-Jan-18
http://www.who.int/leishmaniasis/en/ accessed on 21/11/2017

10. Why Pyrazolopyridine derivatives
were synthesized ?
• The literature reports on antileishmanial leads revealed that the nitrogen
containing heterocycles are very important class of compounds in
antileishmanial drug discovery.
• Indole-containing benzimidamide was identified as potential antileishmanial
compound possessing 10 times better activity.
• Dihydropyridopyrimidine class of compound exhibited in vitro
antileishmanial activity in promastigote and amastigote models.
• Roy et al., reported that the di indolylmethane (DIM) is a potent inhibitor of
L. donovani topoisomerase I enzyme, it binds strongly to the free enzyme and
DIM stabilizes topoisomerase I-DNA cleavage complexes in vitro and in vivo.
1020-Jan-18
Anand,D.R, et al., J. Med. Chem., 2017, 60 (3),1041–1059.

11. Designing of Pyrazolopyridines and
Pyrazolodihydropyridines
1120-Jan-18 Anand,D.R, et al., J. Med. Chem., 2017, 60 (3),1041–1059.

12. Synthesis Of Pyrazolopyridines and
Pyrazolodihydropyridines derivatives
Reagents and conditions (I) Cyanoacetic acid, Ac2O, 60-70 °C, 10 min; (ii) substituted phenylhydrazines, p-TsOH,
EtOH, reflux, 2 h; (iii) CH3COOH, 100-110 °C, 2 h; (iv) DDQ, acetonitrile, RT, 2h
1220-Jan-18 Anand,D.R, et al., J. Med. Chem., 2017, 60 (3),1041–1059.

13. Structure Activity Relationship and
Biological activity
• Several derivatives were synthesized and tested for
their biological activity but only two were found to be
potent i.e. 6d and 6j.
Cont…....1320-Jan-18

14. 1420-Jan-18
Anand,D.R, et al., J. Med. Chem., 2017, 60 (3), 1041–1059.
Cont...

15. CONCLUSION
1520-Jan-18
• A series of pyrazolodihydropyridines and pyrazolopyridines
were synthesized.
• After that it tested for their in vitro antileishmanial activity
against luciferase expressing L.donovani.
• Compounds 6d and 6j were found to be most promising, in
comparison to drug Miltefosine.

16. THANK
YOU
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