Synthesis and evaluation of novel chloropyrrole molecules designed by molecular hybridization of common pharmacophores as potential antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2010.08.026

In an attempt to identify new potential lead as antimicrobial agent, 31 novel chloropyrrole derivatives of aroyl hydrazones and chalcones incorporating common pharmacophore of pyoluteorin derivatives were synthesized. Antimicrobial activity of the synthes

Full text of DOI:10.1016/j.bmcl.2010.08.026

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5681–5685
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of novel chloropyrrole molecules designed
by molecular hybridization of common pharmacophores as potential
antimicrobial agents
Rajesh A. Rane a, Vikas N. Telvekar a,
⇑
a Institute of Chemical Technology, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In an attempt to identify new potential lead as antimicrobial agent, 31 novel chloropyrrole derivatives of
aroyl hydrazones and chalcones incorporating common pharmacophore of pyoluteorin derivatives were
synthesized. Antimicrobial activity of the synthesized compounds was evaluated using broth dilution
technique. Based on biological evaluation data it was observed that activity increases as the number of
chlorines on pyrrole core increases. Few 1H-pyrrole-2-carbohydrazide derivatives shows activity equiv-
alent to the standard drug ciprofloxacin. Thus, these compounds can act as potential lead for further anti-
bacterial studies.
Received 25 March 2010
Revised 4 August 2010
Accepted 5 August 2010
Available online 10 August 2010
Keywords:
Chloropyrrole derivatives
1H-Pyrrole-2-carbohydrazide derivatives
Chalcones
Ó 2010 Elsevier Ltd. All rights reserved.
Antimicrobial agents
Pyoluteorins
The treatment of infectious diseases still remains an important
and challenging problem because of a combination of factors
including emerging infectious diseases and the increasing number
of multi-drug resistant microbial pathogens. There is real per-
ceived need for the discovery of new compounds endowed with
antimicrobial activity, which are distinct from those of well-known
classes of antibacterial agents to which many clinically relevant
pathogens are now resistant.
anti-malerial, antitubercular and antitumor activities.17 These
observations have been guiding for the development of new hydra-
zones that possess varied biological activities. Similarly chalcones
have displayed an impressive array of biological properties among
which antibacterial, antiprotozoal, anti-inflammatory, immuno-
modulatory, nitric oxide inhibition, tyrosinase inhibition, cyto-
toxic, anti-cancer, as well as antifungal and antitubercular
activities have been cited in literature.18
Heterocycles containing pyrrole ring system are found to exhibit
wide spectrum of biological activities and many of them show
appreciable antibacterial,1 antifungal,2 antitumor3, anticonvulsant,4
anti-inflammatory agents,5 and some are used as antibiotics.6 For
several decades, interest in pyrrole derivatives as antimicrobial
agents has led to the preparation and antimicrobial evaluation of
hundreds of such molecules.7–9 Recently separated Celastramycin
A, obtained from Streptomyces Mab-QuH-8 is known to be broad
spectrum antibacterial agent.10,11 Compounds related to Pyoluteo-
rin have shown considerable activity against Staphylococcus aureus,
Shigella flexneri, Tricophyton asteroids, Pseudomonas aeruginosa, Esch-
erichia coli, Proteus vulgaris and herbicidal activity.12–16
On the basis of these literature reports we report synthesis and
evaluation of a novel series of chloropyrrole derivatives designed
by molecular hybridization of common pharmacophores of pyolu-
teorin derivatives (Fig. 1a) with aroyl hydrazones and chalcones.
We have condensed the common 4,5-dichloro-2-acetylpyrrole
moiety from each set of reported pyoluteorin derivatives with ac-
tive pharmacophoric group of reported aroyl hydrazones and chal-
cones to get proposed hybrids. Yet another objective of the study
was to evaluate the effect of chlorine atom/s on antimicrobial
activity of pyrrole core and to optimize the activity through sys-
tematic modification of the substituent on the aromatic ring (
Fig. 1b and c).
Hydrazones possessing an –CONHN@CH– azometine group
constitute an important class of compounds for new drug develop-
ment. Aroyl hydrazone derivatives have been demonstrated to pos-
sess, antimicrobial, anticonvulsant, analgesic, anti-inflammatory,
In the present work, 1H-pyrrole-2-carbohydrazide derivatives
were synthesized utilizing the reaction sequence as shown in
Scheme 1. Trichloroacetylation of pyrrole gave an excellent yield
of 1.19 It was further converted in to ethyl ester which was chlori-
nated using sulfuryl chloride in ether to give ethyl-4-chloro-1H-
pyrrole-2-carboxylate 3.20 4,5-Dichoro-1H-pyrrole-2-carboxylate
5 was synthesized by using chlorine in acetic acid.13 Esters were
converted into corresponding hydrazides 6 which on condensation
⇑
Corresponding author. Tel.: +91 22 24145616.
E-mail address: vikastelvekar@rediffmail.com (V.N. Telvekar).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.026

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R. A. Rane, V. N. Telvekar / Bioorg. Med. Chem. Lett. 20 (2010) 5681–5685
Figure 1a. Reported pyoluteorin derivatives as antimicrobial agents.
dilution technique. The lowest concentration (highest dilution) re-
quired to arrest the growth of bacteria and fungi was regarded as
minimum inhibitory concentration (MIC).25–28 The minimum
inhibitory concentrations are given in Table 1.
The investigation of antibacterial screening data revealed that
all the tested compounds showed moderate to good bacterial inhi-
bition. Compounds 12a, 12b, 12c, 12d, 12e, 12f, and 12i showed
good inhibition against S. aureus and E. coli species. Compounds
11k, 11l, 11m, and 11n exhibited good to moderate antibacterial
activity. Especially compounds 12b, 12d, 12e, 12f, 12i, and 11l
showed activity equivalent to standard against S. aureus. Anti-
fungal activity screening study showed that among all the screened
compounds 12a, 12b, 12c, 12d, 12e, 12f, 12h, and 12i showed good
inhibition against C. albicans.
The chloro atom was found to be beneficial for the antimicrobial
activity. The dichloro analogues were more active than corre-
sponding monochloro analogues. These finding were analogues
with the literature reports on different series where addition of
second atom of halogen to the monochloro or mono bromo com-
pound increased the activity while absence of halogen decreased
activity.29–31 Chlorinated derivatives were reported to be less ac-
tive than brominated one.9,30 Further development of this series
with brominated compounds might be more effective. The number
of chlorine atoms on pyrrole ring seems to be beneficial for activity.
The reason may be attributed to the electron withdrawing nature
of chlorine which will facilitate the interactions with probable ac-
tive site and inhibits the growth of microbes. Aroyl hydrazones
12b, 12c, and 12e were found to be more active than correspond-
ing chalcones 11k,
In summary, using systematic iteration of design, synthesis and
evaluation, 31 new compounds based on the molecular hybridiza-
tion of pyoluteorins with aroyl hydrazones and chalcones were
synthesized and evaluated for their antimicrobial activity. Based
on empirical structure–activity relationship data, it was observed
that 4,5-dicloro-pyrroles derivatives are more active than 4-
chloro/5-chloro-pyrroles. 5-Chloro-pyrrole derivatives are least ac-
tive in corresponding series. 4,5-dichlor-2-pyrroyl hydrazones are
more active than corresponding 4,5-dichloropyrrole chalcones.
Molecules with furan moiety are more active than corresponding
Figure 1b. Scaffold-1: Design of novel 4/4,5-dichloro-N0-arylidene-1H-pyrrole-2-
carbohydrazide analogues using molecular hybridization approach.
with respective aldehydes gives 4/4,5-dichloro-N0-arylidene-1H-
pyrrole-2-carbohydrazide analogues 7 and 12.
2-Acetyl-1H-pyrrole was used as starting material for the syn-
thesis of desired chloropyrrole chalcones derivatives (Scheme 2).
2-Acetyl-1H-pyrrole was chlorinated by sulfuryl chloride in ether
to give corresponding 4/5/4,5-dichloro-2-acetylpyrroles 8, 9, and
10.21 Compounds 8, 9, and 10 were condensed with respective
aldehydes to give chloropyrrole chalcone derivatives 11.22
The Spectral data (IR, 1H NMR, 13C NMR and MS) of all synthe-
sized compounds were in agreement with the proposed structures.
The newly prepared compounds were screened for their antibacte-
rial activity against E. coli (ATCC-25922), S. aureus (ATCC-25923), P.
aeruginosa (ATCC-27853), and Klebsiella pneumoniae (recultured)
bacterial strains by disc diffusion method23,24 and Candida albicans
fungal strain in DMSO by agar dilution method.27,28 The bacterial
and fungal zones of inhibition values are given in Table 1. Mini-
mum inhibitory concentrations (MICs) were determined by broth

R. A. Rane, V. N. Telvekar / Bioorg. Med. Chem. Lett. 20 (2010) 5681–5685
5683
X
Ar
Ar/Het
Y
Ar/Het
N
H
O
X
O
Ar/Het
Cl
Y
N
H
Cl
O
X= Cl/H
Y= Cl/H
Ar/Het
Cl
N
H
Ar/Het
O
N
H
Scaffold 2C
Ar/Het
O
Cl
N
H
Scaffold 2A
O
Scaffold 2B
Figure 1c. Scaffold-2: Design of novel chloropyrrole chalcones using molecular hybridization approach.
Scheme 1. Synthesis of 4/4,5-dichloro-N0-arylidene-1H-pyrrole-2-carbohydrazide analogues.

5684
R. A. Rane, V. N. Telvekar / Bioorg. Med. Chem. Lett. 20 (2010) 5681–5685
Scheme 2. Synthesis of chloropyrrole chalcone anologues.
Table 1
Antimicrobial test results: (MIC lg/ml)
S. No.
E. coli
S. aureus
P. aeruginosa
K. pneumoniae
C. abilcans
7a
7b
7c
7d
7e
7f
7g
7h
14(12.5)
15(12.5)
10(12.5)
12(12.5)
16(12.5)
20(6.25)
21(6.25)
17(12.5)
23(25)
11(12.5)
20(3.125)
19(12.5)
20(3.125)
22(3.125)
18(3.125)
22(6.25)
24(3.125)
16(12.5)
18(12.5)
16(12.5)
12(25)
20(12.5)
10(25)
13(25)
16(12.5)
10(50)
13(12.5)
20(6.25)
21(3.125)
15(6.25)
16(6.25)
25(1.06)
17(12.5)
20(6.25)
18(12.5)
20(12.5)
26(3.125)
17(6.25)
24(3.12)
10(12.5)
24(25)
16(3.125)
24(1.56)
20(6.25)
25(1.56)
24(1.56)
22(1.56)
15(12.5)
26(1.56)
18(12.5)
19(12.5)
13(12.5)
16(12.5)
22(12.5)
16(12.5)
13(25)
14(100)
15(100)
14(100)
16(100)
15(100)
14(100)
14(50)
14(100)
15(100)
18(50)
13(25)
20(25)
18(12.5)
16(25)
18(50)
15(25)
24(25)
15(25)
15(100)
14(100)
16(100)
17(25)
18(25)
—
—
—
—
—
—
—
—
—
20(25)
13(25)
15(25)
20(25)
17(25)
18(25)
18(25)
18(25)
21(25)
23(12.5)
24(12.5)
24(12.5)
24(12.5)
20(12.5)
16(12.5)
22(12.5)
23(12.5)
12(50)
16(50)
12(50)
13(50)
18(50)
15(50)
14(100)
10(100)
14(100)
12(50)
15(50)
14(50)
18(50)
14(50)
25(1.56)
7i
—
12a
12b
12c
12d
12e
12f
12h
12i
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
Standardx
17(100)
18(100)
16(100)
17(100)
20(100)
19(100)
12(100)
20(100)
—
—
—
—
—
—
—
—
—
15(25)
17(25)
—
—
20(12.5)
22(6.25)
25(1.56)
24(3.125)
25(3.125)
20(1.56)
17(100)
15(100)
17(25)
17(25)
16(25)
25(3.125)
18(100)
16(100)
15(100)
18(100)
17(100)
26(1.56)
The representation ‘—’ indicates that bacteria are resistant to the compounds, that is, >100
millimeter. MIC values are given in brackets. MIC ( g/ml) = minimum inhibitory concentration, that is, lowest concentration to com-
pletely inhibit bacterial growth. X = (Standard) ciprofloxacin for antibacterial study and amphotericin B for antifungal study.
lg/ml. Diameter zone of inhibition is in
l

R. A. Rane, V. N. Telvekar / Bioorg. Med. Chem. Lett. 20 (2010) 5681–5685
7. Durham, D. G.; Hughes, C. G.; Rees, A. H. Can. J. Chem. 1972, 50, 3223.
5685
phenyl substituted moieties. Molecules with two chlorines in pyr-
role ring were found to be more active than their monochloro
substituted analogues. These analogues are more active on Gram
positive bacteria than on Gram negative. Molecules show better
activity on bacteria than on fungi. This molecular hybrid provides
potential lead for further studies and development of antimicrobial
molecules.
8. Petruso, S.; Bonanno, S.; Caronna, S.; Ciofalo, M.; Maggio, B.; Schillaci, D. J.
Heterocycl. Chem. 1994, 31, 941.
9. Raimondi, M. V.; Cascioferro, S.; Schillaci, D.; Petruso, S. Eur. J. Med. Chem. 2006,
41, 1439.
10. Pullen, C. et al Planta 2002, 216, 162.
11. Kikuchi, H.; Sekiya, M.; Katou, Y.; Ueda, K.; Kabeya, T.; Kurata, S.; Oshima, Y.
Org. Lett. 2009, 11, 1693.
12. Bailey, D. M.; Johnson, R. E.; Salvador, J. U. J. Med. Chem. 1973, 16, 1298.
13. Bailey, D. M.; Johnson, R. E. J. Med. Chem. 1973, 16, 1300.
14. Rao, K. V.; Reddy, G. C. J. Agric. Food Chem. 1990, 38, 1260.
15. Berkeley, W. C.; Cue, J.; Chamberlain, N. J. Heterocycl. Chem. 1981, 18, 667.
16. Hughes, C. G.; Rees, A. H. J. Med. Chem. 1973, 16, 574.
17. Rollas, S.; Küçükgüzel, Sß. G. Molecules 2007, 12, 1910.
18. Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel, M.; Qazi, G. N.
Bioorg. Med. Chem. Lett. 2005, 15, 3177.
Acknowledgment
V.N.T. and R.A.R. acknowledge AICTE for financial support under
Research Promotion Scheme.
19. Bailey, D. M.; Johnson, R. E.; Albertson, N. F. Org. Syn. 1971, 51, 100.
20. Hodge, P.; Rickards, R. W. J. Chem. Soc. 1965, 459.
21. Ho, C. T.; Jin, Q. Z.; Lee, K. N.; Carlin, J. T. J. Agric. Food Chem. 1982, 30, 362.
22. Tsukerman, S. V.; Izvekov, V. P.; Lavrushin, V. F. Chem. Heterocycl. Compd. 1966,
352.
23. Cruickshank, R.; Duguid, J. P.; Marmion, B. P.; Swain, R. H. A.; Cruickshank, R.,
12th ed.. In Medicinal Microbiology; Churchill Livingstone: London, 1975; Vol. 2.
24. Collins, A. H. Microbiological Methods, 2nd ed.; Butterworth: London, 1976.
25. Schillaci, D.; Petruso, S.; Sciortino, V. Int. J. Antimicrob. Agents 2005, 25, 338.
26. NCCLS Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria, 5th ed.;
NCCLS: Villanova, PA, 2000.
27. Khan, Z. K. In vitro and vivo screening techniques for bioactivity screening and
evaluation, Proc. Int. Workshop UNIDO-CDRI 1997, 210.
28. R. S. Varma, (Ed.), 1998. Antifungal Agents: Past, Present and Future Prospects,
National Academy of Chemistry and Biology, Lucknow, India.
29. Gershon, H.; Parmegiani, R.; Godfrey, P. K. Antimicrob. Agents Chemother. 1972,
373.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.08.026.
References and notes
1. Massa, S.; Di Santo, R.; Mai, A.; Botta, M.; Artico, M.; Panico, S.; Simonetti, G.
Farmaco 1990, 45, 833.
2. Jana, G. H.; Jain, S.; Arora, S. K.; Sinha, N. Bioorg. Med. Chem. Lett. 2005, 15, 3592.
3. Komiyama, K.; Tronquet, C.; Hirokawa, Y.; Funayama, S.; Satoh, O.; Umezawa,
I.; Oishi, S. Jpn. J. Antibiot. 1986, 39, 746.
4. Rostock, A.; Tober, C.; Rundfeldt, C.; Bartsch, R.; Unverferth, K.; Engel, J. V.;
White, H. S. Epilepsy Res. 1997, 28, 17.
5. Sundberg, R. J.. In Comprehensive Heterocyclic Chemistry; Part 3, Pergamon Press,
1984; Vol. 4, p 370.
30. Laatsch, H. et al Chem. Pharm. Bull.. 43 1995, 537.
31. Kumar, P.; Narasimhan, B.; Sharma, D. Arkivoc 2008, 159.
6. Kaneda, M.; Nakamura, S.; Ezaki, N.; Iitaka, Y. J. Antibiot. (Tokyo) 1981, 34, 1366.