Amidine derived 1,3-diazabuta-1,3-dienes as potential antibacterial and antifungal agents

Article abstract of DOI:10.1016/j.bmcl.2004.04.104

Several 1-aryl-2-phenyl-4-piperidino-4-thioalkyl-1,3-diazabuta-1,3-dienes were prepared by the treatment of N-arylimino isothiocyanate with piperidine followed by S-alkylation with alkyl iodides in the presence of dry acetone and potassium hydroxide. The

Full text of DOI:10.1016/j.bmcl.2004.04.104

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3821–3824
Amidine derived 1,3-diazabuta-1,3-dienes as potential antibacterial
and antifungal agents
Preet M. S. Bedi,a,* Mohinder P. Mahajanb and Vijay K. Kapoorc
aDepartment of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India
bDepartment of Applied Chemistry, Guru Nanak Dev University, Amritsar 143 005, Punjab, India
cUniversity Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
Received 4 March 2004; accepted 23 April 2004
Available online 28 May 2004
Abstract—Several 1-aryl-2-phenyl-4-piperidino-4-thioalkyl-1,3-diazabuta-1,3-dienes were prepared by the treatment of N-arylimino
isothiocyanate with piperidine followed by S-alkylation with alkyl iodides in the presence of dry acetone and potassium hydroxide.
The constitution of the products was supported by IR, PMR and mass spectral study. The compounds synthesized were tested in
in vitro against E. coli, S. aureus, P. aeruginosa, B. cereus and B. subtilis and fungal stains, Candida albicans and Aspergillus niger.
Standard drugs were also tested under identical conditions for comparing the results.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
NH2
HN
Antibiotic-resistant pathogens pose an enormous threat
to the treatment of a wide range of serious infections.1
Nosocomial and community-acquired agents have
developed resistance to a wide range of antibiotics2 and
have proven to be highly successful in their ability to
develop resistance mechanisms, often transferable,
against virtually all commonly used antibiotics. The
increasing number of infections caused by methicillin-
resistant Staphylococcus aureus (MRSA), penicillin-
resistant Streptococcus pneumoniae (PRSP) and most
recently, Vancomycin-resistant enterococci (VRE)
emphasize the need for new and alternative antimicro-
bial agents.3 A structure-based approach to design po-
tent and selective agents is an important component of
the modern drug development process.4–6 Pentamidine
(Fig. 1) and berenil (Fig. 2) are aromatic diamidines that
are known to bind to the DNA minor groove at AT
tracts1–10 and to have a long history as antimicrobial
agents.11 These molecules may be viewed as benzami-
dines connected by acyclic linkers. In the 1930s these
type diamidine molecules were studied for their use
against African trypanosomes.12;13 A large number of
NH
HN
Figure 1. Pentamidine.
H
N
N
N
NH2
H2N
NH
HN
Figure 2. Berenil.
synthetic aromatic diamidines, which may be viewed as
derived from 1 and 2 have demonstrated broad spec-
trum antimicrobial activity against several protozoan
and fungal infections.14 The interesting biological
activities exhibited by amidines have prompted us to
synthesize amidine derived, 1,3-diazabuta-1,3-dienes. As
part of our efforts in the development of novel anti-
bacterial agents, we have previously reported novel
series of amidine derived 1,3-diazabuta-1,3-dienes for
this purpose.15;16 In this letter, we primarily focused on
the introduction of a piperidine moiety at C-4 of
* Corresponding author. Tel.: +91-183-2258802-09x3459; fax: +91-
183-2258819-20; e-mail: bedi_preet@yahoo.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.104

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P. M. S. Bedi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3821–3824
1,3-diazabuta-1,3-diene ring system and evaluate them
for their antibacterial and antifungal activity.
3. Antimicrobial activity
The antibacterial activities of the synthesized com-
pounds were determined by agar well diffusion method
as recommended by the National Committee for Clini-
cal Laboratory Standards,20–22 at a concentration of
50 lg/mL using dimethyl sulfoxide (DMSO) as solvent
against Gram positive microorganisms viz. Bacillus
subtilis MTCC 121, Bacillus cereus MTCC 1272,
Staphyloccocus aureus MTCC 1430 and Gram negative
microorganisms such as Escherichia coli MTCC 42 and
Pseudomonas aeruginosa MTCC 1034. Standard anti-
bacterial Ciprofloxacin was also screened under similar
conditions for comparison. While antifungal screening
of the synthesized compounds was determined in a
similar way using Czapek’s agar medium at a concen-
tration of 50 lg/mL against Candida albicans MTCC 183
and Aspergillus niger MTCC 404. Griseofulvin was used
as standard antifungal drug and was subjected to the
same screening pattern for comparison. Solvent control
was maintained in both the studies under similar
2. Chemistry
A novel series of 1-aryl-2-phenyl-4-piperidino-4-thio-
alkyl-1,3-diazabuta-1,3-dienes was conveniently pre-
pared17;18 by the treatment of N-aryl imino iso-
thiocyanates19 4 with secondary amine such as piperidine
have been shown to result in very good yields of 4-[(a-
arylamino) benzylidene thiocarbonyl)] secondary amines
5, commonly referred to as thioureas. The alkylation of
these thioureas with alkyl iodides viz. methyl iodide, ethyl
iodide, butyl iodide and basification of the resultant
hydroiodide salts with 3 N potassium hydroxide resulted
in excellent yields of 1-aryl-2-phenyl-4-piperidino-4-thio-
alkyl-1,3-dizabuta-1,3-dienes 6 (Scheme 1). The 1,3-di-
azabuta-1,3-dienes so obtained (6a–f) were characterized
on the basis of analytical data and spectral evidences.
O
R1
R1
+
SOCl2
+
N
C
NH
C
Cl
3
2
1
(i) Dry Acetone
(ii) NaSCN
R1
R1
Dry Acetone
N
C
N
HN
N
N
S
(Piperidine)
HN
4
S
5
(i) R2I/Acetone
(ii) KOH
R1
6a R1 = H; R2 = CH3
6b R1 = H; R2 = CH2CH3
6c R1 = CH3; R2 = CH3
6d R1 = CH3; R2 = (CH2)3CH3
6e R1 = Cl; R2 = CH3
N
N
SR2
N
6f R1 = CH3; R2 = CH2CH3
6
Scheme 1. Synthesis of 1-aryl-2-phenyl-4-piperidino-4-thioalkyl-1,3-diazabuta-1,3-dienes.

P. M. S. Bedi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3821–3824
Table 1. Antibacterial activity of compounds 6a–f (zone of inhibition in mma)
3823
Compound
E. coli
S. aureus
P. aeruginosa
B. cereus
B. subtilis
6a
6b
+++
+++
+++
+++
+++
+++
+++
)
++
++
++
++
+++
+++
++
++
)
++
+++
++
++
+
++
++
++
++
++
+++
+++
)
+++
+++
+++
++
6c
6d
6e
6f
+
++
++
)
Ciprofloxacin
DMSO
+++
)
a + (11–15 mm), ++ (16–20 mm), +++ (21–25 mm) and ) (inactive).
Table 2. Antifungal activity of compound 6a–f (zone of inhibition in
mma)
The antifungal screening of the prepared 1,3-diazabuta-
1,3-diene compounds revealed that piperidino moiety
was not found to be favourable for antifungal activity.
Compound 6a and 6c did not show any antifungal
activity where as compound 6d and 6e was moderately
active against C. albicans and A. niger. Compound 6b
and 6f was moderately active against C. albicans and
A. niger, respectively. It has been concluded that the
antifungal activity displayed by the compounds 6a–f
were not comparable with the standard drug Griseo-
fulvin.
Compound
C. albicans
A. niger
6a
6b
)
+
)
)
6c
6d
)
++
)
+
6e
6f
+
+
)
+++
+
Griseofulvin
DMSO
+++
)
)
a + (11–15 mm), ++ (16–20 mm), +++ (21–25 mm) and ) (inactive).
Acknowledgements
conditions. The results were presented in Tables 1 and 2,
respectively.
The authors are thankful to Department of Chemistry
and Applied Chemistry, Guru Nanak Dev University,
Amritsar, India for spectral analysis.
4. Results and discussion
References and notes
It has been observed that some of these compounds
exhibited interesting antibacterial activities. Results
reveal that all the synthesized compounds were active
against E. coli comparable to standard drug Ciproflox-
acin. Compound 6a showed maximum activity against
gram positive E. coli, where as by the introduction of
ethyl group in compound 6b, increases its antibacterial
activity against Gram positive and Gram negative bac-
terial strains. More over compound 6b also shows sig-
nificant antibacterial activity against B. cereus, which is
greater than the standard drug as shown in Table 1.
Compound 6c was maximum active against E. coli and
S. aureus whereas moderately active against other bac-
terial strains. Compound 6d, which contains bulkier
butyl group, shows maximum activity E. coli, S. aureus
and P. aeruginosa and emerged out to be a one of potent
antibacterial against Gram negative strains such as
E. coli and P. aeruginosa. Introduction of chlorine in
compound 6e increases its antibacterial spectrum
against Gram negative bacterial strains. Compound 6f
was maximum active against E. coli and B. subtilis.
Solvent DMSO did not show any antibacterial activity.
Therefore the results of antibacterial screening of com-
pounds revealed that 1,3-diazabuta-1,3-dienes having a
piperidino heterocycle showed significant activity com-
parable to standard drug against Gram positive and
Gram negative bacterial strains. The other chemical
moiety found to be favourable towards antibacterial
activity was ethylthio followed by butylthio in the
diazabuta-diene system.
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