Design and synthesis of new hybrid triazine-indole derivatives as potential antimicrobial agents against hospital resistant strains

Article abstract of DOI:10.3987/COM-13-12825

A new series of antimicrobial [2-(5,6-diaryl-1,2,4-triazin-3-yl)-1H-indole] have been synthesized via microwave technology. The synthesized compounds were found to be potent against various clinical isolates of Gram-positive and Gram-negative bacteria as well as hospital resistant strains, MRSA and MSSA when compared to the drugs Cephtriaxone, Gentamycin and Levofloxacin.

Full text of DOI:10.3987/COM-13-12825

HETEROCYCLES, Vol. 87, No. 11, 2013
2385
HETEROCYCLES, Vol. 87, No. 11, 2013, pp. 2385 - 2394. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 2nd September, 2013, Accepted, 4th October, 2013, Published online, 16th October, 2013
DOI: 10.3987/COM-13-12825
DESIGN AND SYNTHESIS OF NEW HYBRID TRIAZINE-INDOLE
DERIVATIVES AS POTENTIAL ANTIMICROBIAL AGENTS AGAINST
HOSPITAL RESISTANT STRAINS
Raed A. Al-Qawasmeh,a,* Monther A. Khanfar,a Mohamad H. Semreen,b
Raed Abu Odeh,c and Taleb H. Al-Telb
a Department of Chemistry, The University of Jordan, Amman 11942-Jordan.
b
Sharjah Institute for Medical Research and Collage of pharmacy, University of
Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
c
College of Health Sciences, Department of Medical Lab Technology, University
of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
* e-mail: r.alqawasmeh@ju.edu.jo
Abstract – A new series of antimicrobial [2-(5,6-diaryl-1,2,4-triazin-3-yl)-
1H-indole] have been synthesized via microwave technology. The synthesized
compounds were found to be potent against various clinical isolates of
Gram-positive and Gram-negative bacteria as well as hospital resistant strains,
MRSA and MSSA when compared to the drugs Cephtriaxone, Gentamycin and
Levofloxacin.
The rise of multidrug resistance has prompted renewed interest in the development of novel antimicrobial
agents. It is not surprising that pathogenic species have adopted survival mechanisms to the existing
antimicrobial drugs. The increase incidence of bacterial resistance to a large number of antibacterial
agents such as glycopeptides, sulfonamides, β-lactams, nitroimidazole, quinolones, tetracyclins,
chloroamphenicol, macrolides is becoming a major concern.1,2 The emergence of multidrug resistance
Gram-positive and Gram-negative bacteria considered to be the current drive to produce new agents
targeting novel sites that may circumvent resistance is critical to the long-term control of bacterial
infection.3
Sepsis caused by methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of severe
diseases and mortality worldwide. Many organs are vulnerable to MRSA infections, including skin,
kidney, and other organs, resulting in serious life-threatening pathogenesis.4 Community- and

2386
HETEROCYCLES, Vol. 87, No. 11, 2013
nosocomial-acquired MRSA are common pathogens with resistance towards various classes of antibiotics,
including methicillin, penicillin, and amoxicillin.5
Therefore, in 2010 the Infectious Disease Society of America (IDSA) has issued a challenge, which seeks
a global commitment to create antibiotic research and development enterprise powerful enough to
produce 10 new systemic antibiotics by the year 2020.6
Indole nucleus and it is derivatives are considered as privileged scaffold in medicinal chemistry,7-10 that
constitutes an important class of therapeutic agents, including anticancer,11 antioxidant,12
antirheumatoidal,13 and anti-HIV,14 and also play a vital role in immune system drugs.15 Indole moiety
was reported as a main component of potent antimicrobial agents.16 Another important hetercyclic
compound of particular importance is the triazine moiety. Triazine and their deriviatives possess a variety
of biological activities such as hypertension and inhibition of platelets,17 antileukemic,18
antiinflammatory,19 and potent neuroprotective agents.20 The triazine moiety also is a main structural
element in antimalarial,21 anticancer,22 antifungal,23 anticonvulsant,24 antibacterial,25 and antiviral,26
compounds. Certain compounds containing a 1,2,4-triazine nucleus have been reported to possess
pesticidal,27 neuropharmacologica,28 analgesic and antidepressant properties.29
In continuation of a program directed toward drug design and discovery (references from our work
below), we report herein the synthesis of new hybrid scaffolds combining indole and substituted triazine
to achieve maximum in vitro antimicrobial activity against Gram-negative and Gram-positive bacteria,
including hospital resistant strains.30-33
Chemistry
The newly prepared compounds were synthesized starting from the commercially available indole
2-carboxylic acid 1, which was converted to the ethyl ester 2 via conventional Fisher esterefication
(Scheme 1). Hydrazide derivative 3 was produced under the microwave condition via reaction of the ester
in presence of excess hydrazine hydrate to deliver hydrazide 3. With the later in hand, it was anticipated
to construct the heterocycles triazines applying Biotage Initiator 2.5 under microwave assisted organic
synthesis as described in Scheme 2. Thus, hydrazide 3 was mixed with symmetrical benzil compounds
4a-h in acetic acid and ammonium acetate to produce after work up highly pure compounds in fairly good
yields.
O
O
O
i
ii
N
N
N
OEt
NHNH2
OH
H
H
H
1
2
3
Scheme 1. Synthesis of the hydrazide compound: i) EtOH/H2SO4, MW. ii) NH2NH2, EtOH, MW

HETEROCYCLES, Vol. 87, No. 11, 2013
2387
All the synthesized compounds were identified through physical analysiss. HRMS-ESI gave exact
molecular ions for all the compounds. The structures of the new derivatives were unambiguously
1
13
determined from their corresponding H and C-NMR spectra. Chemical shifts of aromatic protons on
triazine core appeared as expected in the range of δ 7.00–9.50 ppm, with multiplicities and coupling
1
constants reflecting the substitution pattern in each compound. H NMR spectra of the synthesized
derivatives showed multiplet signals in the aromatic region typical for non-symmetrically substituted
triazine. The NH protons of the indole moiety appeared at 9.50–9.60 ppm for all the synthesized
13
compounds. C NMR spectra of the new compounds 5a-h were in full agreement with the proposed
structures. DEPT experiments were used equivocally to confirm the proposed structures.
Ar
O
O
AcONH4
N
3
+
Ar
AcOH/MW
Ar
Ar
N
N N
H
4a: Ar = Ph
5a: Ar = Ph
4b
: Ar = 4-F-Ph
: Ar = 4-Br-Ph
5b
: Ar = 4-F-Ph
: Ar = 4-Br-Ph
4c
4d
5c
5d
: Ar = 4-Me-Ph
: Ar = 4-Me-Ph
4e: Ar = 4-MeO-Ph
4f: Ar = 2-pyridyl
5e: Ar = 4-MeO-Ph
5f: Ar = 2-pyridyl
4g
4h
: Ar = 2-thinyl
: Ar = 2-furyl
5g
5h
: Ar = 2-thinyl
: Ar = 2-furyl
Scheme 2. Synthesis of the triazine compounds 5a-h
Antibacterial studies
The title compounds were evaluated in vitro against three Gram-positive Staphylococcus epidermidis,
methicillin-sensitive Staphylococcus aureus ATCC 25923 (MSSA), methicillin-resistant Staphylococcus
aureus ATCC33591 (MRSA), two standard Gram negative bacteria: Escherichia coli ATCC 25922 and
Pseudomonas aeruginosa ATCC 27583. In addition, clinical (hospital acquired) isolates for E. coli,
Klebsiella pneuomoniae (K.p), Pseudomonas aeruginosa (P.a) and Proteus vulgaris (P.v) were also used
for comparison. Broth micro-dilution method, using Mueller-Hinton broth medium (Himedia), was used
to determine the antimicrobial activity.34-35 Gentamicin, levofloxacin and cephatriaxone were used as the
positive control. The obtained results, depi cted in Table 1 as MIC values, revealed that many of the new
scaffolds could effectively, to some extent, inhibit the growth of all tested strains in vitro.
As indicated in Table 1, MIC values in the range of 1.85–62.50 µg/mL against both Gram-positive and
Gram-negative strains were found. Interestingly, almost all the tested derivatives indicated appreciable
activities against MRSA and MSSA species. Compounds 5e, 5f and 5h were found to be two folds more
potent against MRSA than the positive controls used in this study. On the other hand, compounds 5b,
5e and 5f were found to be four times more potent against MSSA compared to cephtriaxone and

2388
HETEROCYCLES, Vol. 87, No. 11, 2013
gentamycine controls. However, compound 5h possessed twice the activity against MSSA compared to
cephtriaxone and gentamycine.
Compounds 5b, 5c and 5e gave the best inhibitory activity against most of the Gram-negative strains
tested in this study. Compounds 5b and 5e possess stronger antimicrobial activities compared to the
reference antimicrobial agents cephtriaxone, gentamycin and levofloxacin.
Table 1. In vitro antibacterial activity (MIC µg/mL) of compounds 5a-h
Compound
Gram-negative
Gram-positive
E.Coli a E. Coli* K.p*
P.v*
P.ab
P.a*
MRSA c MSSA d S.
Epidermidis
5a
5b
5c
5d
5e
5f
R
31.25
7.5
15.75
7.5
7.5
31.25
7.5
62.5
1.85
1.85
62.5
1.85
3.75
62.5
7.5
15.75
1.85
15.75
15.75
7.5
62.5
7.5
62.5
1.85
7.5
1.85
7.5
3.75
15.75
31.25
3.75
15.75
31.25
7.5
7.5
31.25
31.25
7.5
15.75
31.25
15.75
62.5
31.25
15.75
R
7.5
15.75
1.85
7.5
15.75
3.75
7.5
62.5
3.75
3.75
62.5
7.5
62.5
7.5
15.75
15.75
3.85
7.85
7.85
7.85
7.5
3.75
31.25
1.85
1.85
15.5
3.75
5g
5h
31.25
15.75
154.75
7.5
R
7.5
Cephtriaxone 1.85
Gentamycin 15.5
Levofloxacin 7.85
15.5
R
R
3.75
7.5
15.5
15.5
15.5
15.5
15.5
7.85
15.5
7.5
1.85
7.5
62.5
1.85
a (ATCC25922); b (ATCC 27583); c (ATCC 33591); d (ATCC 25923); * These bacteria species were clinical
isolates, supplied by the Clinical Hospital of Rashid-Dubai, United Arab Emirates
At this point in time, structural-activity relationships could be drawn around triazine aryl moieties of the
designed compounds. It is evident that the bromine and methoxy substituted aryl moieties were the
most active compounds. Besides, the fluorophenyl armed triazine was found to be the most potent
among others.
In conclusion, a series of new indole-triazine hybrids were successfully synthesized from commercially
available starting materials applying microwave assisted synthesis. The in vitro antibacterial evaluation of
these motifs showed that the synthesized compounds could effectively inhibit the growth of all tested
bacteria including methicillin-resistant and multidrug resistant S. aureus and some of these lead scaffolds
displayed two to four fold stronger antimicrobial activities in comparison with the positive controls used
in this study.

HETEROCYCLES, Vol. 87, No. 11, 2013
2389
These findings form the foundation for redirected efforts aimed at developing novel analogs as preclinical
trials candidates as antibacterial. Furthermore, the mechanism of action of these compounds is under
investigations in our laboratories.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker Avance III-500 MHz spectrometer with TMS as an internal
standard. 13C NMR spectra were recorded at 125 MHz using a Bruker Avance III-500 MHz spectrometer
with TMS as an internal standard. Chemical shifts were reported as δ-values in ppm. The multiplicities of
carbon atoms were determined from DEPT experiments. High resolution Mass spectra (HRMS) were
recorded in positive ion mode by Electrospray Ionization using a Bruker Daltonics Apex IV, 7.0 T Ultra
Shield Plus. The samples were dissolved in chloroform, diluted in spray solution (MeOH/water 1:1 v/v +
0.1% formic acid) and infused using a syringe pump with a flow rate of 2 µL/min. External calibration
was conducted using arginine cluster in a mass range m/z 175-871. For all HRMS data, mass error:
0.00–0.50 ppm. Melting points (mp) were determined on an Electrothermal Melting point Apparatus and
were uncorrected in °C. Solvents used in this study were obtained from Scharlau, Fluka and Aldrich. All
reactions were monitored by thin layer chromatography (TLC) using Merck aluminum plates pre-coated
with silica gel PF254; 20 × 20 × 0.25 mm, and detected by visualization of the plate under UV lamp (λ =
254 or 365 nm). Spots were also detected by spraying with anisaldehyde- sulphuric acid in EtOH,
followed by heating to 140 °C. All microwave reactions were performed using Biotage Initiator 2.5, the
closed Teflon vessel was irradiated with variable power to keep a constant temperature over the reaction
time.
Ethyl 1H-indole-2-carboxylate (2)
A mixture of indole-2-carboxylic acid (1) (0.161 mg, 1 mmol), EtOH (4-5 mL), and concentrated sulfuric
acid (0.5 mL) was placed in 5 mL sealed vial and subjected to coherent microwave radiation for 20 min at
140 °C. The reaction mixture was poured on crushed ice and then neutralized with sodium bicarbonate
solution, the precipitated product was recrystallized from ethanol to yield 180 mg of a colorless powder,
95% yield.
1H-Indole-2-carbohydrazide (3)
A mixture of ethyl 1H-indole-2-carboxylate (2) (189 mg, 1 mmol), EtOH (3-4 mL), and hydrazine
hydrate (10 mmol) was placed in 5 mL sealed vial and subjected to coherent microwave radiation for 15
min at 140 °C. The reaction mixture was poured on crushed ice and the precipitated product was
recrystallized from ethanol to produce a quantitative product.

2390
HETEROCYCLES, Vol. 87, No. 11, 2013
2-(5,6-Diaryl/heteroaryl-1,2,4-triazin-3-yl)-1H-indoles 5a-h
General procedure for the synthesis of 5a-h
A mixture of 1H-indole-2-carbohydrazide (3) (249 mg, 1 mmol), acetic acid (4 mL), ammonium acetate
(10 eq), and benzil compound (1.2 mmol) was placed in 5 mL sealed vial and subjected to two successive
coherent microwave radiation for 20 min at 140 °C. The reaction mixture was poured on a mixture of
ammonia and crushed ice to produce a yellow precipitate which was further separated using TLC to
produce pure compounds (40-75% yield).
2-(5,6-Diphenyl-1,2,4-triazin-3-yl)-1H-indole (5a)
This derivative was synthesized according to the general procedure above. Yield: 75%; Yellow soild; mp
163-164 °C. 1H NMR (500 MHz, DMSO-d6) δ 7.71 (bd, J = 8 Hz, 1H), 7.66 (bd, J = 8 Hz, 1H), 7.65 (bs,
13
1H), 7.41-7.60 (m, 11H), 7.26 (bt, J = 7 Hz, 1H), 7.10 (bt, J = 7 Hz, 1H). C NMR (125 MHz,
DMSO-d6): 157.8, 156.3, 155.6, 138.8, 136.1, 136.0, 133.6, 131.1, 130.3, 129.8, 128.9, 128.8, 128.5,
+
124.4, 124.3, 122.0, 120.5, 113.0, 106.1. ESI-HRMS: Calc. for C23H17N4 [M+H]+: 349.14477. Found:
349.14479.
2-(5,6-Bis(4-fluorophenyl)-1,2,4-triazin-3-yl)-1H-indole (5b)
This derivative was synthesized according to the general procedure above. Yield: 70%; Yellow soild; mp
170-172 °C. 1H NMR (500 MHz, CDCl3): δ 9.56 (bs, 1H), 7.77 (bd, J = 7 Hz, 1H), 7.69 (m, 3H), 7.62 (d,
J = 5.3 Hz, 1H), 7.61 (d, J = 5.3 Hz, 1H), 7.52 (bdd, J = 0.8, 1 Hz, 1H), 7.35 (m, 1H), 7.20 (m, 1H);
13
7.11-7.15 (m, 4H). C NMR (125 MHz, CDCl3): δ 165.4, 164.7, 163.4, 162.7, 156.9, 154.88, 154.1,
132.6, 132.1, 132.0, 131.5, 131.4, 131.4, 131.3, 128.7, 125.0, 122.2, 120.8, 116.1, 116.0, 115.9, 115.8.
+
ESI-HRMS: Calc. for C23H15F2N4 [M+H]+: 385.12593. Found: 385.12593.
2-(5,6-Bis(4-bromophenyl)-1,2,4-triazin-3-yl)-1H-indole (5c)
This derivative was synthesized according to the general procedure above. Yield 65%; Yellow soild; mp
1
235-236 °C. H NMR (500 MHz, CDCl3): δ 9.53 (bs, 1H), 7.77 (bd, J = 8 Hz, 1H), 7.69 (m, 1H),
7.48-7.60 (m, 9H); 7.34-7.37 (m, 1H), 7.19-7.22 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 57.0, 154.9,
153.9, 137.7, 134.2, 134.1, 132.5, 132.4, 132.1, 132.0, 131.2, 128.9, 126.0, 125.1, 124.52 122.3, 120.9,
+
111.8, 107.4. ESI-HRMS: Calc. for C23H15Br2N4 [M+H]+: 504.96580. Found: 504.96588.
2-(5,6-Di(p-tolyl)-1,2,4-triazin-3-yl)-1H-indole (5d)
This derivative was synthesized according to the general procedure above. Yield 65%; Yellow soild; mp
1
215-216 °C. H NMR (500 MHz, CDCl3): δ 9.60 (bs, 1H), 7.77 (d, J = 8 Hz, 1H), 7.68 (bd, J = 1.5 Hz,

HETEROCYCLES, Vol. 87, No. 11, 2013
2391
1H), 7.60 (d, J = 8 Hz, 2H), 7.52 (bd, J = 8 Hz, 2H), 7.51 (d, J = 9 Hz, 1H), 7.33 (t, J = 7 Hz, 1H),
7.18-7.23 (m, 5 H); 2.43 (s, 6H). 13C NMR (500 MHz, CDCl3): δ 156.7, 155.9, 155.1, 141.3, 139.7, 137.5,
133.1, 132.9, 132.8, 129.8, 129.3, 129.3, 129.3, 128.8, 124.8, 124.7, 122.13, 120.6, 111.7, 106.6, 21.5,
+
21.4. ESI-HRMS: Calc. for C25H21N4 [M+H]+: 377.17607. Found: 377.17613.
2-(5,6-Bis(4-methoxyphenyl)-1,2,4-triazin-3-yl)-1H-indole (5e)
This derivative was synthesized according to the general procedure above. Yield 70%; Yellow soild; mp
1
209-211 °C. H NMR (500 MHz, CDCl3): δ 9.54 (s, 1H), 7.97 (bd, J = 9 Hz, 2H), 7.77 (bd, J = 8 Hz,
1H); 7.70 (d, J = 9 Hz, 2H), 7.66 (bs, 1H), 7.60 (d, J = 9 Hz, 2H); 7.51 (bd, J = 8 Hz, 2H), 7.34 (bt, J = 8
Hz, 1H), 7.19 (bt, J = 8 Hz, 1H), 7.09 (bd, J = 12 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H). ESI-HRMS: Calc.
+
for C25H21N4O2 [M+H]+: 409.16590. Found: 409.16589.
2-(5,6-Di(pyridin-2-yl)-1,2,4-triazin-3-yl)-1H-indole (5f)
This derivative was synthesized according to the general procedure above. Yield 45%; Yellow soild; mp
158-159 °C. 1H NMR (500 MHz, CDCl3): δ 9.66 (bs, 1H), 8.41 (d, J = 5 Hz, 1H), 8.37 (d, J = 5 Hz, 1H),
8.23 (d, J = 8 Hz, 1H), 7.90-7.94 (m, 2H), 7.73-7.78 (m, 2H), 7.51 (bd, J = 8 Hz, 1H), 7.28-7.37 (m, 4H),
7.27 (bt, J = 8 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 157.3, 155.6, 154.8, 154.7, 154.6, 148.8, 148.6,
137.7, 137.0, 136.9, 132.6, 128.8, 125.0, 124.6, 124.5, 123.9, 122.3, 120.8, 111.8, 107.6. ESI-HRMS:
+
Calc. for C21H15N6 [M+H]+: 351.13527. Found: 351.13497.
2-(5,6-Di(thiophen-2-yl)-1,2,4-triazin-3-yl)-1H-indole (5g):
This derivative was synthesized according to the general procedure above. Yield 40%; Yellow soild; mp
178-179 °C. 1H NMR (500 MHz, CDCl3): δ 9.51 (bs, 1H), 7.65-7.66 (m, 2H), 7.61 (dd, J = 5, 1 Hz, 1H),
7.58 (dd, J = 1, 4 Hz, 2H), 7.50-7.52 (m, 2H), 7.35 (bt, J = 8 Hz, 1H), 7.16-7.21 (m, 2H), 7.10 (dd J = 4, 5
Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 156.2, 149.3, 148.2, 139.2, 137.6, 137.2, 132.5, 132.4, 131.8,
+
131.3, 129.3, 129.2, 128.7, 124.9, 122.2, 120.8, 111.8, 107.1. ESI-HRMS: Calc. for C19H13N4S2 [M+H]+:
361.05761. Found: 361.05802.
2-(5,6-Di(furan-2-yl)-1,2,4-triazin-3-yl)-1H-indole (5h)
This derivative was synthesized according to the general procedure above. Yield 40%; Yellow soild; mp
1
162-164 °C. H NMR (500 MHz, CDCl3): δ 9.61 (bs, 1H), 7.77 (d, J = 8 Hz, 1H), 7.72 (d, J = 1.5 Hz,
1H), 7.69 (d, J = 1.5 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7.34 (bt, J = 8 Hz, 1H),
7.20 (bt, J = 8 Hz, 1H), 7.13 (d, J = 3.4 Hz, 1H), 7.03 (d, J = 3.5 Hz, 1H), 6.68 (dd, J = 2, 3 Hz, 2H); 6.64
(dd, J = 2, 3.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 156.4, 148.6, 146.7, 144.5, 144.3, 143.9, 137.6,

2392
HETEROCYCLES, Vol. 87, No. 11, 2013
132.6, 128.7, 124.7, 122.2, 120.7, 117.9, 113.1, 112.8, 112.2, 111.7, 107.2. ESI-HRMS: Calc. for
+
C19H13N4O2 [M+H]+: 329.10330. Found: 329.10313.
In vitro antimicrobial procedure
Gram-positive strains namely; Staphylococcus epidermidis, methicillin-sensitive Staphylococcus aureus
ATCC 25923 (MSSA), methicillin-resistant Staphylococcus aureus ATCC33591 (MRSA), two standard
Gram-negative bacteriaial strains namely; Escherichia coli ATCC 25922, Pseudomonas aeruginosa
ATCC 27583 along with the clinical (hospital acquired) isolates for E. coli, Klebsiella pneuomoniae,
Pseudomonas aeruginosa and Proteus vulgaris were used to evaluate the minimum inhibitory
concentration of designed compounds.34,35 Thus, the bacteria were inoculated into Luria broth medium
containing 1% tryptone, 0.5% yeast extract, 0.5% sodium chloride. The pH of the medium was adjusted
to 7.2 with sterile phosphate buffered saline and incubated at 37 °C for 24 h. The optical density of the
bacteria from mid-log phase of growth was measured at 540 nm and diluted in fresh medium to obtain an
optical density of 0.004 (corresponding to 5×105 colony forming units/mL). To each well of the ELISA
plate, 200 µL of diluted bacterial suspension was added and graded concentrations (0.2-500 µg/50 µL) of
the synthesized compounds and standard antibiotics (Cephtriaxone, Gentamycin and Levofloxacin) in
20% H2O/DMSO were added and incubated at 37 °C for 24 h. At the end of incubation the effect of the
drugs on the growth of organisms was monitored by measuring the optical density at 540 nm using an
ELISA reader. The MIC was defined as the lowest concentration of the antibiotic or test sample allowing
no visible growth.
ACKNOWLEDGEMENTS
This work was supported by grants from the Deanship of Scientific Research, The University of Jordan,
Amman 11942, Jordan and The Ministry of Higher Education and Research, National Research
Foundation, United Arab Emirates, grant number: RSA-1108-00192.
REFERENCES (AND NOTES)
1. R. Leclercq, Clin. Microbiol. Infect., 2009, 15, 224.
2. G. Cornaglia and G. M. Rossolini, Clin. Microbiol. Infect., 2009, 15, 218.
3. N. M. Haste, C. C. Hughes, D. N. Tran, W. Fenical, P. R. Jensen, V. Nizet, and M. E. Hensler,
Antimicrob. Agents Chemother., 2011, 55, 3305.
4. J. F. Kokai-Kun, T. Chanturiya, and J. J. Mond, J. Antimicrob. Chemother., 2007, 60, 1051.
5. L. Cantoni, A. Wenger, M. P. Glauser, and J. J. Bille, Infect. Dis., 1989, 159, 989.
6. R. J. Guidos, Clin. Infect. Dis., 2010, 50, 1081.

HETEROCYCLES, Vol. 87, No. 11, 2013
2393
7. R. J. Sundberg, 'Indoles', Academic Press, San Diego, 1996.
8. D. J. Faulkner, Nat. Prod. Rep., 2001, 18, 1.
9. M. Bandini, A. Melloni, and A. Umani-Ronchi, Angew. Chem. Int. Ed., 2004, 43, 550.
10. J. F. Austin and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124, 1172.
11. S. Suzan and E. Buyukbingol, Il Farmaco, 2000, 55, 246.
12. E. Buyukbingol, S. Suzan, and G. Klopman, Il Farmaco, 1994, 49, 443.
13. S. Suzan and E. Buyukbingol, Il Farmaco, 1998, 53, 525.
14. P. M Lieberman, A. Wolfer, P. Felsner, D. Hofer, and K. Schauenstein, Int. Arch. Allergy Immunol.,
1997, 112, 203.
15. D. Page, H. Yang, W. Brown, C. Walpole, M. Fleurent, M. Fyfe, F. Gaudreault, and S. St-Onge,
Bioorg. Med. Chem. Lett., 2007, 17, 6183.
16. R. A. Al-Qawasmeh, M. Huesca, V. Nedunuri, R. Peralta, J. Wright, Y. Lee, and A. Young, Bioorg.
Med. Chem. Lett., 2010, 20, 3518.
17. A. Monge, J. Palop, C. Ramizrez, and F. A. E. Font, Eur. J. Med. Chem., 1998, 16, 83.
18. I. M. Labounta, N. H. Eshba, and H. M. Salama, Farm. Sci. Ed., 1998, 16, 29.
19. K. Abd. Al-Samii, J. Chem. Tech. Biotech., 1992, 53, 143.
20. M. J. Leach and M. S. Nobls, Eur. Pat. Appl. EP459, 829 (Chem. Abstr., 1992, 116, 128970x).
21. L. C. March, G. S Bajwa, J. Lee, K. Wasti, and M. M. Joullie, J. Med. Chem., 1976, 19, 845.
22. Z. El-Gendy, J. Morsy, H. Allimony, and R. Abdel-Monem, Phosphorous, Sulphur Silicon Relat.
Elem., 2003, 178, 2055.
23. J. Wieczorek, M. Modarski, A. Rykowski, and P. Nantka-Nimrski, Arch Immunol Ther Exp (Warsz),
1980, 28, 727.
24. D. L. Trepanier, E. R. Wagner, G. Harris, and D. Allan, J. Med. Chem., 1966, 90, 881.
25. K. Srinivas, U. Srinivas, R. Jayathirtha, K. Bhanuprakash, K. Harakishore, and U. S. N. Murthy,
Bioorg. Med. Chem. Lett., 2005, 15, 1121
26. V. L. Rusinov, E. N. Ulomskii, O. N. Chapakhin, M. M. Zubairnov, A. B. Kapustin, N. I. Mitin, M. I.
Zhiravetskii, and I. A. Vinograd, Pharmaceut. Chem. J., 1990, 24, 640.
27. A. S. Gupta, T. Bhattacharya, K. Hajela, K. Shankar, and S. Ahmad, Pesticide Science, 1985, 16, 65.
28. S. S. Smagin, V. E. Bogachev, A. K. Vakubovskii, S. E. Methalova, T. P. Privol’neva, V. V.
Chugunon, and E. F. Lavretskaya, Pharmaceut. Chem. J., 1975, 9, 222.
29. C. Rubat, P. Coudert, S. Marvel, J. Fialip, and J. Couquelet, J. Pharm. Pharmacol., 1999, 49, 1019.
30. T. H. Al-Tel, M. H. Semreen, R. El-Awady, R. Abu-Odeh, M. Saber, R. A. Al-Qawasmeh, and S.
Chouaib, Curr. Med. Chem., 2013, 20, 1445.
31. T. H. Al-Tel, M. H. Semreen, R. A. Al-Qawasmeh, M. F. Schmidt, R. El-Awadi, M. Ardah, R.

2394
HETEROCYCLES, Vol. 87, No. 11, 2013
Zaarour, S. N. Rao, and O. El-Agnaf, J. Med. Chem., 2011, 54, 8373.
32. T. H. Al-Tel, R. A. Al-Qawasmeh, and R. Zaarour, Eur. J. Med. Chem., 2011, 46, 1874.
33. A. J. M. Rasras, T. H. Al-Tel, A. F. Al-Aboudi, and R. A. Al-Qawasmeh, Eur. J. Med. Chem., 2011,
45, 2307.
34. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests
for Bacteria That Grow Aerobically: approved standard-8th ed., M07-A8. Clinical and Laboratory
Standards Institute, Wayne, PA, 2008.
35. J. M. Andrews, J. Antimicrob. Chemother., 2001, 48, 5.