Synthesis and antimycobacterial activity of highly functionalized tetrahydro-4(1H)-pyridinones

Article abstract of DOI:10.1016/j.bmcl.2011.05.032

A series of 35 2e,3e,6e-triaryltetrahydro-4(1H)-pyridinones, 2e,3e,5e,6e-tetraaryltetrahydro-4(1H)-pyridinones and their N-nitroso and N-cyano analogs have been prepared. All these 35 compounds obtained were screened for their in vitro activity against My

Full text of DOI:10.1016/j.bmcl.2011.05.032

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3881–3884
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antimycobacterial activity of highly functionalized
tetrahydro-4(1H)-pyridinones
Velanganni Paul Alex Raja a, Subbu Perumal a, , Perumal Yogeeswari b, Dharmarajan Sriram b
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science–Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
series of 35 2e,3e,6e-triaryltetrahydro-4(1H)-pyridinones, 2e,3e,5e,6e-tetraaryltetrahydro-4(1H)-
Received 7 April 2011
Revised 9 May 2011
Accepted 10 May 2011
Available online 15 May 2011
pyridinones and their N-nitroso and N-cyano analogs have been prepared. All these 35 compounds
obtained were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB).
Among them, the N-nitrosopyridinones are found to be more active against MTB than the corresponding
N-CN analogs, which, in turn, were slightly more active than NH analogs. In particular, the N-nitroso com-
pounds, 3d, 4b and 4e with halogen-bearing phenyl rings at 2,6-positions showed maximum activity
Keywords:
N-Nitrosation
N-Cyanation
Tetrahydro-4(1H)-pyridinones
Antimycobacterial activity
with MIC values of 3.97, 3.11 and 3.11 lM, being more efficacious than the first line anti-TB drugs, cip-
rofloxacin, ethambutol and pyrazinamide. A general trend has also been discerned in all the three classes
of NH, N-CN and N-NO compounds, in each of which those bearing four aryl rings display higher activity
than that having three analogously substituted aryl rings disclosing that lipophilicity could be an impor-
tant factor underlying antimycobacterial activity.
Ó 2011 Elsevier Ltd. All rights reserved.
Tuberculosis (TB), a disease considered for long as substantially
eradicated in developed countries, has resurged dramatically,
establishing itself as one of the most dreaded infectious diseases
resulting in the highest number of human deaths worldwide.1–3
Approximately one-third of the world’s population (ꢀ1.86 billion)
is infected4 with Mycobacterium tuberculosis (MTB). According to
World health organization (WHO) estimates, there are about 8 mil-
lion new active cases of TB, resulting in nearly 2 million deaths per
year mostly from developing countries.4,5 In addition, the number
of people contracting TB is continuously on the rise, as their im-
mune systems are impaired by immunosuppressive drugs, sub-
stance abuse and HIV. The contemporary treatment of TB
involves administration of multi-drug regimen over a long period
of time.6,7 This leads to patient noncompliance and rapid emer-
gence of multi-drug resistant and extensively drug resistant TB
(MDR- and XDR-TB) strains, which impede the discovery and the
development of new drugs.8–10 In the last 50 years, only a few
drugs have been approved by the Food and Drug Administration
(FDA) for treating TB. This discloses the difficulties associated with
the discovery and clinical testing of new agents and the lack of
pharmaceutical industry research in this area.11 Hence, the discov-
ery of fast-acting effective new drugs possessing new mechanisms
of action to cure TB is imperative.
Piperidones and their derivatives exhibit important biological
activities such as anticancer,12 anticonvulsant,13 antiinflamma-
tory14 and local anaesthetic.15 It is pertinent to note that in our re-
cent studies, we have come across several heterocycles comprising
piperidine rings displaying significant antimycobacterial activity.16
In these studies, the nitrogen of the piperidine ring system as well
as the groups attached to it are found to significantly contribute to
and influence the activity. As the CN and NO groups linked to ring
nitrogen could significantly alter the electron density of the ring
nitrogen as well as the stereochemistry of piperidones, it was
considered important from structure–activity point of view, to
investigate the antimycobacterial activity of a library of NH,
N-CN and N-NO-tetrahydro-4(1H)-pyridinones. Consequently, we
have synthesized a library of thirty five highly functionalized NH,
N-CN and N-NO-tetrahydro-4(1H)-pyridinones (Scheme 1),
screened them for antimycobacterial activities in vitro against M.
tuberculosis H37Rv (MTB) and report the results in this Letter. This
work stems as a continuation of our recently embarked research on
the synthesis of novel heterocycles and their screening against
antimycobacterial activities.16,17
The 2e,3e,6e-triaryltetrahydro-4(1H)-pyridinones 1 and 2,3,5,6-
tetraaryltetrahydro-4(1H)-pyridinones
2 were prepared by a
literature method18 and their N-nitroso derivatives 3 and 4, respec-
tively, were obtained by the reaction of 1 and 2 with sodium nitrite
and hydrochloric acid in chloroform–water medium in good yields
(Scheme 1, vide Supplementary data).
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.032

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V. P. A. Raja et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3881–3884
H
Ar
Ph
Ar
NaNO2, HCl
CHCl3, H2O
H
N
H
N
Ph
O
H
O
H
O
Ar
HN
3
Ar
Ph
O
1
K CO ,
BrCN
2
3
Ar
Acetone
N
Ar
C
N
H
5
H
Ar
NaNO2, HCl
CHCl3, H2O
Ph
Ar
N
N
H
Ph
O
H
O
O
Ph
Ar
HN
Ar
Ph
4
Ph
O
2
K CO ,
BrCN
3
2
Ar
Acetone
Ph
N
Ar
C
6
N
Scheme 1. Synthesis of tetrahydro-4(1H)-pyridinones 3–6
The crystals of the pyridin-4-ones for X-ray crystallographic
studies were obtained by recrystallization from ethanol–ethyl
acetate mixture. In the case of unsymmetrical N-nitroso-2,3,6-tria-
ryltetrahydro-4(1H)-pyridinones 3, the partial double bond charac-
ter of the N-NO functionality gives rise to two isomeric forms,
syn- and anti-, and hence two sets of chemical shifts for the protons
were obtained in NMR spectra. In solid state, these compounds
adopt only one form as revealed by X-ray crystallographic study
of 3c (Fig. 1) which shows that the 2,6-bis(4-methylphenyl)-
Figure 2. ORTEP diagram of 4c.
N-nitroso-3-phenyltetrahydro-4(1H)-pyridinone adopts
a boat
conformation.19 The N-nitroso-2,3,5,6-tetraaryltetrahydro-4(1H)-
pyridinones 4, being symmetrical, give only one set of NMR signals.
The X-ray crystallographic study of the compounds, viz., 4c20
(Fig. 2), 4d21 (Fig. 3), 4e22 (Fig. 4), 4f23 (Fig. 5), and 4g24 (Fig. 6)
show that they all adopt a boat conformation in solid state.
Among the compounds 4c–4g, 4e and 4g adopt a slightly
twisted boat conformation, while the other compounds adopt al-
most a true boat form. The N-cyanation of 1 and 2 was carried
Figure 3. ORTEP diagram of 4d.
out by reacting them with cyanogen bromide and potassium
carbonate in acetone (vide Supplementary data), which afford
the N-cyano-2e,3e,6e-triaryltetrahydro-4(1H)-pyridinones 5 and
N-cyano-2e,3e,5e,6e-tetraaryltetra-hydro-4(1H)-pyridinones
6
(Scheme 1), respectively, in good yields. Both the N-cyanotri and
tetraaryl compounds were found to exist in chair form as evident
from the coupling constants of the vicinal protons of the heterocy-
clic rings in these compounds and from the X-ray crystallographic
study of one representative compound 6a25 (Fig. 7).
Figure 1. ORTEP diagram of 3c.

V. P. A. Raja et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3881–3884
3883
Figure 6. ORTEP diagram of 4g.
Figure 4. ORTEP diagram of 4e.
Figure 7. ORTEP diagram of 6a.
compounds with four aryl rings possess higher activity than that
of analogously substituted compounds bearing three aryl rings.
These results suggest that lipophilicity could be an important con-
tributory factor for activity. In both series 1 and 2, compounds with
halophenyl rings at 2,6-positions display enhanced efficacy against
MTB as evident from MIC values of 1 having aryl rings with p-F
(34.39
(7.12
l
M), o- and p-Cl (31.54
l
M) and 2 having aryls with p-F
Figure 5. ORTEP diagram of 4f.
l
M) and o- and p-Cl (13.23
l
M). Among N-nitroso com-
pounds 3 and 4 also, compounds with halogens in the aryl rings
at 2,6-positions show greater efficacy against MTB as seen from
MIC values of 3d with p-flourophenyl rings (3.97
4e, respectively, with p- and o-chlorophenyl rings (3.11
l
M) and 4b and
M).
The compounds 1a–6d were screened for their in vitro antimy-
cobacterial activity against MTB by agar dilution method for the
determination of minimum inhibitory concentration (MIC) in
duplicate at 7.40 pH. At this pH, the amine functionality of the
compounds cannot be significantly protonated, and hence the free
amine is responsible for the activity. The MIC is defined as the min-
imum concentration of compound required to completely inhibit
the bacterial growth. The MICs of the synthesized compounds
along with that of the standard drugs for comparison are reported
in Table 1 and Figure 8.
l
Among the N-H (1 and 2), N-NO (3 and 4) and N-CN (5 and 6) com-
pounds, the activity is found to be in the order: N-NO > N-CN > N-H
disclosing that the N-substituent has a significant effect on the
activity against MTB.
A comparison of the MIC values of all the compounds synthe-
sized with that of the currently employed anti-TB drugs (Table 1
and Fig. 8) reveals that (i) 28 compounds have MIC values in the
range 3.11–34.39
lM showing higher potency against MTB than
the anti-TB drug pyrazinamide (MIC 50.8
viz., 2e, 3b, 3d, 4b, 4c, 4e, 4f and 4g have their MIC values falling
in the range 3.11–7.35 with better activity than that of the drug
ethambutol (MIC 7.6 lM), (iii) three compounds have their MIC
l
M), (ii) 8 compounds,
An examination of the data presented in Table 1 reveals that the
NH-tetraaryltetrahydropyridinones 2 show higher activity than
their triarylanalogs 1 bearing similarly substituted aryl rings at
2,6-positions. In a similar fashion, both N-nitroso and N-cyano

3884
V. P. A. Raja et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3881–3884
Table 1
and the Department of Science and Technology, New Delhi for
Antimycobacterial activities of 1a–6d against MTB.
funds under IRHPA program for the purchase of a high resolution
NMR spectrometer. V.P.A.R. thanks the Council of Scientific and
Industrial Research, New Delhi for the award of a Senior Research
Fellowship.
Compound Ar
MIC (
l
M) Compound Ar
MIC (lM)
1aa
4-ClC6H4
4-MeC6H4
4-FC6H4
2-ClC6H4
2- MeC6H4
31.54
70.32
34.39
31.54
70.32
3e
4aa
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
6a
6b
6c
6d
2-MeC6H4
C6H5
4-ClC6H4
4-MeC6H4
4-MeOC6H4 12.68
2-ClC6H4
2-MeC6H4
2-MeOC6H4
C6H5
4-ClC6H4
4-MeC6H4
4-MeOC6H4 30.30
4-FC6H4
C6H5
8.14
14.45
3.11
1ba
1ca
1da
6.79
Supplementary data
1ea
1fa
2-MeOC6H4 64.52
3.11
6.79
6.35
70.93
29.66
65.70
2aa
C6H5
4-ClC6H4
4-MeC6H4
61.95
13.23
28.96
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.05.032.
2ba
2ca
2da
4-MeOC6H4 26.96
2ea
4-FC6H4
2-ClC6H4
2- MeC6H4
7.12
13.23
28.96
References and notes
2fa
2ga
16.09
58.33
25.12
12.56
27.37
1. World Health Organization, Tuberculosis Fact Sheet, 2006, No. 104; please see:
http://www.who.int/mediacentre/factsheets/fs104/en/.
2. Ballell, L.; Field, R. A.; Duncan, K.; Young, R. J. Antimicrob. Agents Chemother.
2005, 49, 2153.
3. Janin, Y. L. Bioorg. Med. Chem. 2007, 15, 2479.
4. Dye, C.; Scheele, S.; Dolin, P.; Pathania, V.; Raviglione, M. C. J. Am. Med. Assoc.
1999, 282, 677.
5. Snider, D. E. J.; Raviglione, M.; Kochi, A. In Global Burden of Tuberculosis,
Tuberculosis: Pathogenesis, Protection and Control; Bloom, B., Ed.; (Am. Soc.
Microbiol., Washington, DC, 1994; p 3).
2ha
2-MeOC6H4 26.96
3aa
C6H5
17.53
7.35
8.14
3.97
0.4
4-ClC6H4
2-ClC6H4
2-MeC6H4
3b
3c
3d
4-ClC6H4
4-MeC6H4
4-FC6H4
Isoniazid
Ciprofloxacin
Ethambutol
Pyrazinamide
7.6
50.8
4.7
a
Known compounds.
6. Clarck, C.; Jacobs, M.; Appelbaum, P. C. J. Clin. Microbiol. 1998, 36, 3579.
7. Davidson, P. T.; Le, H. Q. Drugs 1992, 43, 651.
8. Vincent, T. A. Int. J. Antimicrob. Agents 2000, 16, 317.
9. Tan, Y. T.; Tillett, D. J.; Mckay, I. A. Mol. Med. Today 2000, 6, 309.
10. MacManus, M. C. Am. J. Health-Syst. Pharm. 1997, 54, 1420.
11. O’Brien, R. J.; Nunn, P. P. Am. J. Respir. Crit. Care Med. 2001, 163, 1055.
12. Ileana, B.; Dobre, V.; Niculescu-Duvaz, I. J. Prakt. Chem. 1985, 327, 667.
13. Reddy, P. A.; Woodward, K. E.; Mcllheran, S. M.; Hsiang, B. C. H.; Latifi, T. N.;
Hill, M. W. J. Med. Chem. 1997, 40, 44.
14. Ranise, A.; Schenone, S.; Bruno, O.; Bondavalll, F.; Filiippelll, W.; Falcone, G.;
Rivaldi, B., II Farmaco 2001, 56, 647.
15. Perumal, R. V.; Adiraj, M.; Shanmugapandiyan, P. Indian Drugs 2001, 38,
156.
16. (a) Ranjith Kumar, R.; Perumal, S.; Senthil Kumar, P.; Yogeeswari, P.; Sriram, D.
J. Med. Chem. 2008, 51, 5731; (b) Ranjith Kumar, R.; Perumal, S.; Senyhil KUmar,
P.; Yogeeswari, P.; Sriram, D. Tetrahedron 2008, 64, 2962; (c) Balamurugan, K.;
Jeyachandran, V.; Perumal, S.; Manjashetty, T. H.; Yogeeswari, P.; Sriram, D.
Eur. J. Med. Chem. 2010, 45, 682; (d) Karthikeyan, S. V.; Perumal, S.; Krithika, A.
S.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2009, 19, 3006; (e) Ranjith
Kumar, R.; Perumal, S.; Manju, S. C.; Bhatt, P.; Yogeeswari, P.; Sriram, D. Bioorg.
Med. Chem. Lett. 2009, 19, 3461; (f) Ranjith Kumar, R.; Perumal, S.; Senyhil
Kumar, P.; Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2009, 44, 3821; (g)
Ranjith Kumar, R.; Perumal, S.; Menéndez, J.C.; Yogeeswari, P.; Sriram, D.
Bioorg. Med. Chem. (in press).
17. (a) Balamurugan, K.; Jeyachandran, V.; Perumal, S.; Menéndez, J. C. Tetrahedron
2011, 67, 1432; (b) Indumathi, S.; Perumal, S.; Menéndez, J. C. J. Org. Chem.
2010, 75, 472; (c) Balamurugan, K.; Perumal, S.; Kumar Reddy, A. S.;
Yogeeswari, P.; Sriram, D. Tetrahedron Lett. 2009, 50, 6191; (d) Indumathi, S.;
Ranjith Kumar, R.; Perumal, S. Tetrahedron 2007, 63, 1411; (e) Srinivasan, M.;
Perumal, S. Tetrahedron 2007, 63, 2865; (f) Karthikeyan, S. V.; Perumal, S.
Tetrahedron Lett. 2007, 48, 2261; (g) Raja, V. P. A.; Perumal, S. Tetrahedron 2006,
62, 4892; (h) Balamurugan, K.; Perumal, S.; Menéndez, J. C. Tetrahedron 2011,
67, 3201.
18. Gdaniec, M.; Milewska, M. J.; Połonski, T. J. Org. Chem. 1995, 60, 7411.
19. Suresh, J.; Raja, V. P. A.; Krishnakumar, R. V.; Perumal, S.; Ravikumar, K.;
Natarajan, S. Anal. Sci. 2006, 22, x223.
20. Suresh, J.; Raja, V. P. A.; Perumal, S.; Natarajan, S. Acta Crystallogr. 2006, E62,
o3307.
21. Natarajan, S.; Krishnakumar, R. V.; Nandhini, M. S.; Raja, V. P. A.; Perumal, S.;
Ravikumar, K. Acta Crystallogr. 2005, E61, o359.
22. Suresh, J.; Raja, V. P. A.; Natarajan, S.; Perumal, S.; Mostad, A.; Krishnakumar, R.
V. Acta Crystallogr. 2005, E61, o3391.
23. Suresh, J.; Raja, V. P. A.; Krishnakumar, R. V.; Natarajan, S.; Perumal, S.; Mostad,
A. Acta Crystallogr. 2005, E61, o2458.
24. Suresh, J.; Raja, V. P. A.; Krishnakumar, R. V.; Natarajan, S.; Perumal, S.; Mostad,
A. Acta Crystallogr. 2005, E61, o3050.
Figure 8. Antimycobacterial activity of 1–6 and standard drugs.
in the range 3.11–3.97
ciprofloxacin (MIC 4.7
l
M disclosing higher activity than the drug
lM) and all the compounds being less po-
tent than isoniazid (MIC 0.4).
This work describes the synthesis and antimycobacterial
screening of a library of 35 highly functionalized tetrahydro-
4(1H)-pyridinones against M. tuberculosis H37Rv (MTB). The N-
nitrosopyridinones display greater activity than the corresponding
N-H and N-CN pyridinones. The presence of halogens in aryl rings
enhances the activity rendering three compounds with higher po-
tency than three standard anti-TB drugs, viz., ciprofloxacin, etham-
butol and pyrazinamide.
Acknowledgments
25. Suresh, J.; Raja, V. P. A.; Natarajan, S.; Perumal, S.; Mostad, A.; Krishnakumar, R.
V. Acta Crystallogr. 2006, E62, o1295.
S.P. thanks the University Grants Commission, New Delhi, for
funding for a major research project [F. No. 36-155/2008(SR)]