Synthesis of chiral macrocyclic or linear pyridine carboxamides from pyridine-2,6-dicarbonyl dichloride as antimicrobial agents

Article abstract of DOI:10.3390/molecules15096588

A series of chiral linear and macrocyclic bridged pyridines has been prepared starting from pyridine-2,6-dicarbonyl dichloride (2). The coupling of 1 with D-alanyl methyl ester gave 2,6-bis-D-alanyl pyridine methyl ester (3). Hydrazinolysis of 3 with hydrazine hydrate afforded bis-hydrazide 4. The latter was reacted with thiophene-2-carbaldehyde, phthalic anhydride or cyclohexanone to afford bis-carboxamide pyridine derivatives 5-7, respectively. Compound 4 was coupled with p-methoxy- or p-nitroacetophenone to yield compounds 8 and 9. In addition, 4 was reacted with 1,2,4,5-benzenetetracarboxylic acid dianhydride or 1,4,5,8-naphthalenetetracarboxylic acid dianhydride to afford the macrocyclic octacarboxaamide pyridines 10 and 11. The detailed synthesis, spectroscopic data and antimicrobial screening for the synthesized compounds are reported.

Full text of DOI:10.3390/molecules15096588

Molecules 2010, 15, 6588-6597; doi:10.3390/molecules15096588
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Chiral Macrocyclic or Linear Pyridine
Carboxamides from Pyridine-2,6-dicarbonyl Dichloride as
Antimicrobial Agents
Rashad A. Al-Salahi, Mohamed A. Al-Omar and Abd El-Galil E. Amr *
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451,
Saudi Arabia
* Author to whom correspondence should be addressed; E-Mail: aamr1963@yahoo.com.
Received: 26 August 2010; in revised form: 6 September 2010 / Accepted: 7 September 2010 /
Published: 20 September 2010
Abstract: A series of chiral linear and macrocyclic bridged pyridines has been prepared
starting from pyridine-2,6-dicarbonyl dichloride (2). The coupling of 1 with D-alanyl
methyl ester gave 2,6-bis-D-alanyl pyridine methyl ester (3). Hydrazinolysis of 3 with
hydrazine hydrate afforded bis-hydrazide 4. The latter was reacted with thiophene-2-
carbaldehyde, phthalic anhydride or cyclohexanone to afford bis-carboxamide pyridine
derivatives 5-7, respectively. Compound 4 was coupled with p-methoxy- or p-nitroaceto-
phenone to yield compounds 8 and 9. In addition, 4 was reacted with 1,2,4,5-benzenetetra-
carboxylic acid dianhydride or 1,4,5,8-naphthalenetetracarboxylic acid dianhydride to
afford the macrocyclic octacarboxaamide pyridines 10 and 11. The detailed synthesis,
spectroscopic data and antimicrobial screening for the synthesized compounds are reported.
Keywords: synthesis; chiral macrocyclic; pyridine-2,6-dicarbonyl dichloride;
antimicrobial activity
1. Introduction
Synthesis of chemical modifications of existing antibacterial agents in order to generate novel
molecules with better therapeutic properties is necessary because of the emergence of multidrug
resistant bacteria [1]. In continuation of our previous investigations [2-4], we have previously reported

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the synthesis and biological activity screening of some dipicolinic acid bis-L-amino acid hydrazide
derivatives [3] and their corresponding acids [5]. Compounds of this kind have attracted considerable
attention as inhibitors of ribonucleoside diphosphate reductase [6]. Synthetic macrocyclic peptides are
still the subject of intensive research with respect to their therapeutic applications [7], as well as their
binding properties [8]. We also demonstrated that some peptido-heterocyclic derivatives exhibit a
general ionophoric potency towards divalent cations [9] and are useful for assembling novel
thiocyanate-selective membrane sensors [10]. On the other hand, Schiff base and other heterocyclic
derivatives were reported to possess diverse biological activities, such as antibacterial [11-14] and
anti-inflammatory [15-17] properties. Recently, we have demonstrated the significance of 2,6-di-
substituted pyridine derivatives as biologically active congeners [18-23]. In view of these observations
and as a continuation of our previous work in peptido-heterocyclic chemistry, we have synthesized
some new compounds containing amino acid and hetero-organic moieties, and tested them for selected
biological activities.
2. Results and Discussion
2.1. Chemistry
D-Alanyl methyl ester was initially coupled with 2,6-dipicolinic acid (1) (Mixed Anhydride Method,
Method A] [5] or with pyridine-2,6-dicarboyl dichloride (2) via the conventional acid chloride method
(Methid B) [3] to give the corresponding bis-ester 3. Hydrazinolysis of 3 with hydrazine hydrate in
absolute ethanol afforded the corresponding bis-hydrazide 4 (Scheme 1).
Scheme 1. Synthetic routes to compounds 3 and 4.
SOCl2
O
O
O
O
N
N
DMF
Cl
Cl
OH
OH
2
1
Me
NH2. HCl
Method B
TEA
*
CH2Cl2
/
COOMe
O
Me
NH2. HCl
*
O
Method A
COOMe
N
CH2Cl2 / TEA
ClCOOEt
NH
HN
Me
O
Me
O
*
*
O
O
3
Me
Me
O
O
N
NH2NH2.H2O
EtOH
NH
*
HN
Me
Me
O
*
HN
O
NH
NH2
NH2
4

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The reaction of bishydrazide 4 with thiophene-2-carbaldehyde in refluxing ethanol afforded the
corresponding hydrazone 5, but when it was reacted with phthalic anhydride in refluxing glacial acid it
gave the corresponding imide 6. In a similar way, treatment of bis-hydrazide 4 with carbonyl
compounds, namely, cyclohexanone, p-methoxyacetophenone or p-nitroacetophenone in refluxing
ethanol in the presence of few drops of glacial acetic acid afforded the corresponding bis-(cyclohexyl
tetraamide)pyridine derivative 7, bis-(substituted aryl tetraamide)pyridine derivatives 8 and 9,
respectively (Scheme 2).
Scheme 2. Synthetic routes to compounds 5-9.
O
O
O
O
N
N
HN
Me
O
Me
NH
HN
Me
NH
Me
*
*
*
*
O
O
O
NH
N
HN
N
HN
N
NH
N
O
O
O
O
S
S
5
6
O
O
O
CHO
S
EtOH
4
AcOH
O
X
COMe
EtOH/AcOH
EtOH/AcOH
O
O
O
O
N
N
HN
Me
Me
NH
*
Me
NH
HN
Me
*
*
*
O
O
NH
N
HN
N
HN
N
O
O
NH
N
Me
Me
7
8, X = OMe
9, X = NO2
X
X

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Condensation of the same hydrazide 4 with selected tetraacid dianhydrides, namely, 1,2,4,5-
benzenetetracarboxylic acid dianhydride or 1,4,5,8-naphthalenetetracarboxylic acid dianhydride in
refluxing acetic acid afforded the corresponding macrocyclic octaamide-tetraimide pyridine
derivatives 10 and 11, respectively (Scheme 3).
Scheme 3. Synthetic routes to compounds 10 and 12.
O
O
O
O
O
O
O
O
O
O
O
O
4
AcOH
AcOH
O
O
O
O
N
N
Me
O
NH
NH
HN
Me
O
Me
NH
HN
HN
Me
O
*
*
*
*
HN
O
NH
O
O
N
N
O
O
N
O
O
O
O
N
O
O
O
O
O
O
O
N
N
N
N
O
O
NH
NH
HN
HN
O
O
NH
NH
HN
HN
O
*
*
Me
Me
*
*
Me
Me
N
O
O
N
O
O
10
11
Table 1. Melting points, crystallization solvents, yields, molecular formulae and molecular
weights of compounds 3-9.
Comp
. No.
3
4
5
6
7
8
9
Mp
(ºC)
Cryst.
Solv.
EtOH/diethyl ether
EtOH
Yield
(%)
75 [A]; 80 [B]
[α]30
Molecular Formula
(Mol. Wt.)
D
[MeOH]
+ 68
+ 45
+ 32
+ 8
+ 18
+34
+ 54
+ 24
+ 16
148-250
193-195
157-159
302-304
135-137
139-140
152-154
201-203
232-234
C15H19N3O6 (337.13)
C13H19N7O4 (337.33)
C23H23N7O4S2 (525.60)
C29H23N7O8 (597.54)
C25H35N7O4 (497.59)
C31H35N7O6 (601.65)
C29H29N9O8 (631.60)
C46H34N14O16 (1038.85)
C54H38N14O16 (1138.96)
76
65
80
65
70
65
60
65
EtOH
AcOH/ether
EtOH/diethylether
EtOH
EtOH
DMF/H2O
DMF/H2O
10
11
1
The structures of newly synthesized compounds 3-11 were confirmed by IR, H-NMR, 13C-NMR
and mass spectra.

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2.2. Antimicrobial Testing
Preliminary biological activity screening of the synthesized compounds at 50 μg/mL has been
performed against microorganisms representing Gram-positive bacteria (Bacillus subtilis and
Staphylococcus aureus), Gram-negative bacteria (Escherichia coli) and fungi (Candida albicans),
using the bioassay technique of antibiotics [24] specified in US Pharmacopeia. From Table 2, it
appears that the synthesized compounds 3-11 have significant antimicrobial activities, with 5, 6, 7, 9,
10 and 11 having higher antimicrobial activities than that of the other prepared compounds. On the
other hand, compounds 3, 5, 7, 9, 10 and 11 exhibited interesting high antifungal activities, in addition
to their antibacterial activities. Ciprofloxacin and ketaconazole were used as antibacterial and
antifungal reference drugs, respectively.
Table 2. Antimicrobial activities of the new synthesized compounds 3-11.
Inhibition zone in mm (at 50 µg/mL)
Compound No.
Gram positive bacteria
Bacillus subtilis S. aureus
Gram negative bacteria
Fungi
Escherichia coli
C. albicans
14
16
14
25
23
19
13
20
19
20
23
-ve
18
20
18
25
25
22
19
25
24
22
23
-ve
19
14
19
20
30
21
16
24
20
21
25
-ve
-ve
16
-ve
17
-ve
20
-ve
14
16
15
-ve
23
1
3
4
5
6
7
8
9
10
11
Ciprofloxacin
Ketaconazole
2.3. Structure-Activity Relationship (SAR)
From the results above (Table 2), we can conclude that pyridine and amide moieties are essential
for antimicrobial activity. In the present work, we can suggest that the antimicrobial activity is due to:
•
•
•
The presence of nitrogen heterocyclic rings.
The presence of the amide linkage groups generally enhancing the activity.
The difference in activity between the compounds which is due to the indicated
subsistents in the used reagents of the molecule.
3. Experimental
3.1. General
Melting points (ºC) were measured in open glass capillaries using a Barnstead 9001 Electrothermal
melting point apparatus and are uncorrected. NMR spectra were obtained on a Bruker AC 500 Ultra
1
Shield NMR spectrometer (Bruker, Fällanden, Switzerland) operating at 500 MHz for H and 125
MHz for 13C; the chemical shifts are expressed in δ (ppm) downfield from tetramethylsilane (TMS)

Molecules 2010, 15
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used as internal standard. Electrospray ionization mass spectra (ESI-MS) were recorded on a Waters
QuatroMicro triple quadrupole tandem mass spectrometer at 4.0 and 3.5 kV for positive and negative
ions, respectively. Elemental analyses (C, H, N, Cl, S) were in full agreement with the proposed
structures within ± 0.4% of the theoretical values. Monitoring the reactions and checking the purity of
the final products were carried out by thin layer chromatography (TLC) using silica gel precoated
aluminum sheets (60 F254, Merck) and visualization with ultraviolet light (UV) at 365 and 254 nm.
3.2. Chemistry
3.2.1. Synthesis of 2,6-bis-(methyl-D-alanylcarbonyl)pyridine carboxylate (3)
Method A: To a stirred cold mixture (-15 ºC) of 2,6-pyridine dicarboxylic acid (1, 0.167 g, 1 mmol) in
cold dry tetrahydrofuran (100 mL) and ethyl chloroformate (0.216 g, 2 mmol), triethylamine (0.202 g,
2 mmol) was added, then after 10 min., D-alanyl methyl ester (0.206 g, 2 mmol) was added. The
reaction mixture was stirred at -15 ºC for 3 h then for 12 h at r.t. The formed triethylamine
hydrochloride was filtered off, and the solvent was evaporated under reduced pressure. The obtained
residue was dissolved in 150 mL dichloromethane, washed with water, 1N hydrochloric acid, 1N
sodium bicarbonate and finally with water and dried over anhydrous calcium chloride. Solvent was
evaporated under reduced pressure to dryness and the obtained solid was crystallized to give 3.
Method B: To a solution of D-alanyl methyl ester (0.206 g, 2 mmol), pyridine-2,6-dicarbonyl
dichloride (2, 0.204 g, 1 mmol) in dichloromethane (15 mL) was added at -10 ºC with stirring.
Triethylamine (0.2 mL, 2 mmol) was added dropwise to the reaction mixture with stirring in order to
keep the reaction mixture slightly basic (pH ~ 8). Stirring was maintained for 3 hours at (-15 ºC) and
12 h at r.t.. The reaction mixture was then washed with water, 1N hydrochloric acid, 1N sodium
bicarbonate and finally with water and dried over anhydrous calcium chloride. Solvent was evaporated
under reduced pressure to dryness and the obtained solid was crystallized to give 3. IR (KBr, cm-1): ν
1
3284 (NH), 1742 (C=O), 1680 (C=O). H-NMR (DMSO-d6): δ 1.56 (d, 6H, 2 CH3), 3.80 (s, 6H,
2OCH3), 4.70-4.81 (m, 2H, 2 CH), 8.05 (s, 2H, 2 NH exchangeable with D2O), 8.29-8.37 (m, 3H,
pyrid-H). 13C-NMR: 18.20, 48.31, 52.60, 125.19, 138.93, 148.35, 162.89, 173.28. MS, m/z (%): 337
(M+, 4), 306 (24), 275 (100), 204 (36), 133 (18), 105 (65), 77 (86).
N2,N6-Bis(1-hydrazinyl-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (4). A mixture of 3 (0.24 g,
1 mmol) and hydrazine hydrate (0.8 mL, 16 mmol) in absolute ethanol (50 mL) was refluxed for 6 h.
Excess solvent was evaporated under reduced pressure to dryness and the obtained residue was
triturated with ethanol, the obtained solid was crystallized to give 4. IR (KBr, cm-1): ν 3853-3280 (NH,
NH2), 1661 (C=O). 1H-NMR (DMSO-d6): δ 1.44 (d, 6H, 2 CH3), 2.51 (s, 4H, 2NH2, exchangeable with
D2O), 4.52-4.55 (m, 2H, 2 CH), 8.15-8.21 (m, 3H, pyrid-H), 9.16 (d, 2H, 2 NH exchangeable with
D2O), 9.27 (s, 2H, 2 NH exchangeable with D2O). 13C NMR: 17.90, 47.54, 124.52, 139.18, 148.74,
162.93, 171.19. MS, m/z (%): 339 (M++2, 100), 306 (32), 275 (56), 235 (44), 133 (100), 105 (72), 102 (65).
N2,N6-Bis(1-oxo-1-(2-(thiophen-2-ylmethylene)hydrazinyl)propan-2-yl)pyridine-2,6-dicarboxamide
(5). A solution of 4 (0.34 g, 1 mmol) and thiophene-2-carbaldehyde (0.224 g, 2 mmol) in absolute

Molecules 2010, 15
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ethanol (100 mL) was refluxed for 6 h. The solvent was concentrated under reduced pressure, the
obtained solid was filtered off, dried and crystallized to afford 5. IR (KBr, cm-1): ν 3854-3676 (NH),
1
1669 (C=O). H-NMR (DMSO-d6): δ 1.50 (d, 6H, 2CH3), 4.56-4.57 (m, 2H, 2CH), 7.18, 7.19 (s, 2H,
2CH=N), 7.44-7.73 (m, 6H, Ar-H), 8.20-8.32 (m, 3H, pyrid-H), 9.14, 9.63 (2s, 4H, 4NH exchangeable
with D2O). 13C NMR: 14.06, 16.68, 48.22, 60.62, 124.78, 125.03, 125.16, 128.01, 128.25, 128.81,
129.33, 130.97, 131.51, 133.76, 139.05, 139.41, 139.73, 145.52, 148.32, 155.77, 159.55, 163.10,
172.33. MS, m/z (%): 523 (M+-2, 2), 510 (4), 480 (5), 457 (3), 355 (8), 221 (100), 207 (12), 193 (15),
150 (45), 105 (18), 94 (5), 78 (15).
N2,N6-Bis(1-(1,3-dioxoisoindolin-2-ylamino)-1-oxopropan-2-yl)-pyridine-2,6-dicarboxamide (6). A
suspension of 4 (0.34 g, 1 mmol) and phthalic anhydride (0.3 g, 2 mmol) in glacial acetic acid (50 mL)
was refluxed for 3 h. The solvent was evaporated under reduced pressure, the residue was solidified
with diethyl ester. The obtained solid was filtered off, dried and crystallized to give 6. IR (KBr, cm-1):
ν 3853-3675 (NH), 1661 (C=O). 1H-NMR (DMSO-d6): δ 1.60 (d, 6H, 2CH3), 3.36-3.50 (m, 2H, 2CH),
7.88-8.07 (m, 8H, Ar-H), 8.23-8.42 (m, 3H, pyrid-H), 9.81, 9.99 (2s, 4H, 4NH exchangeable with
D2O). 13C NMR: 20.48, 47.18, 123.72, 124.05, 124.90, 129.40, 135.30, 135.32, 160.20, 167.92, 171.90.
MS, m/z (%): 597 (M+, 0.16), 569 (12), 462 (5), 433 (4), 413 (8), 278 (6), 267 (6), 207 (45), 162 (55),
104 (100), 78 (18), 55 (20).
N2,N6-Bis(1-(2-cyclohexylidenehydrazinyl)-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (7). To a
solution of cyclohexanone (0.196 g, 2 mmol) in absolute ethanol (50 mL) in the presence of few drops
glacial acetic acid, compound 4 (0.34 g, 1 mmol) was added with stirring. The reaction mixture was
heated under reflux for 6 h, and evaporated under reduced pressure to dryness. The obtained residue
was solidified with n-hexane, the solid formed was filtered off, dried and crystallized to give 7. IR
1
(KBr, cm-1): ν 3268 (NH), 2934 (CH-aliphatic), 1664 (C=O). H-NMR (DMSO-d6): δ 1.56 (d, 6H,
2CH3), 1.62-1.65 (m, 6H, 3CH2, cyclohexyl ring), 2.28-2.30 (m, 4H, 2CH2, cyclohexyl ring), 3.66-3.76
(m, 2H, 2CH), 8.25-8.56 (m, 3H, pyrid-H), 8.96, 10.15 (2s, 4H, 4NH exchangeable with D2O). 13C
NMR: 15.80, 23.85, 26.45, 35.10, 46.96, 124.58, 139.08, 148.14, 162.42, 163.65, 172.25. MS, m/z (%):
497 (M+, 0.1), 480 (0.1), 465 (0.2), 238 (16), 220 (100), 192 (55), 146 (35), 110 (62), 45 (54).
3.2.2. Synthesis of N2,N6-Bis(1-(2-(1-(4-substituted-phenyl)ethylidene)hydrazinyl)-1-oxopropan-2-
yl)pyridine-2,6-dicarboxamides 8 and 9
A mixture of 4 (0.34 g, 1 mmol) and an acetophenone derivative, namely, p-methoxy- or p-nitro-
acetophenenone (2 mmol) in absolute ethanol (100 mL) was refluxed for 6 h in the presence of glacial
acetic acid (2 mL). The reaction mixture was concentrated under reduced pressure, the solid formed
was collected by filtration, and purified by crystallization to give 8 and 9.
N2,N6-Bis(1-(2-(1-(4-methoxyphenyl)ethylidene)hydrazinyl)-1-oxopropan-2-yl)pyridine-2,6-dicarbox-
1
amide (8). IR (KBr, cm-1): ν 3269 (NH), 2997 (CH-aliphatic), 1663 (C=O). H-NMR (DMSO-d6): δ
1.36-1.42 (m, 6H, 2CH3), 1.68 (s, 6H, 2CH3), 3.68 (s, 6H, 2OCH3), 4.22-4.28 (m, 2H, 2CH), 7.42-7.84
(m, 8H, Ar-H), 8.16-8.34 (m, 3H, pyrid-H), 9.34, 10.05 (2s, 4H, 4NH exchangeable with D2O). 13C

Molecules 2010, 15
6595
NMR: 17.60, 18.15, 52.95, 56.84, 114.05, 126.12, 129.65, 124.80, 138.96, 149.55, 161.85, 162.32,
168.70, 177.80. MS, m/z (%): 601 (M+, 10), 552 (1), 512 (2), 252 (12), 235 (10), 221 (100), 193 (25),
178 (24), 150 (54), 78 (15).
N2,N6-Bis(1-(2-(1-(4-nitrophenyl)ethylidene)hydrazinyl)-1-oxopropan-2-yl)pyridine-2,6-dicarbox-
1
amide (9). IR (KBr, cm-1): ν 3311 (NH), 1669 (C=O). H-NMR (DMSO-d6): δ 1.42-1.48 (m, 6H,
2CH3), 1.72 (s, 6H, 2CH3), 4.18-4.30 (m, 2H, 2CH), 7.24-7.85 (m, 8H, Ar-H), 8.22-8.42 (m, 3H,
pyrid-H), 9.40, 10.15 (2s, 4H, 4NH exchangeable with D2O). 13C NMR: 17.45, 18.23, 52.88, 56.85,
114.35, 125.98, 129.48, 125.10, 138.92, 148.95, 162.05, 162.40, 168.65, 176.95. MS, m/z (%): 631
(M+, 8), 585 (4), 537 (6), 509 (12), 357 (8), 275 (100), 245 (35), 189 (62), 133 (46), 77 (48).
3.2.3. Synthesis of macrocyclic octaamide tetraimides 10 and 11
A suspension of 4 (0.34 g, 1 mmol) and 1,2,4,5-benzenetetracarboxylic acid dianhydride or 1,4,5,8-
naphthalene tetracarboxylic acid dianhydride (1 mmol) in acetic acid (50 mL) was refluxed for 7 h.
The obtained solid was collected by filtration, and crystallized to give 10 and 11.
Macrocyclic octaamide tetraimide 10. IR (KBr, cm-1): ν 3853-3675 (NH), 1661-1668 (C=O). 1H-NMR
(DMSO-d6): δ 1.42-1.72 (m, 12H, 4CH3), 3.54-3.68 (m, 4H, 4CH), 7.75 (s, 4H, Ar-H), 8.18-8.30 (m,
6H, 2 pyrid-H), 9.78, 10.05 (2s, 8H, 8NH exchangeable with D2O). 13C NMR: 18.95, 48.05, 123.88,
124.92, 129.52, 135.45, 136.10, 161.20, 168.92, 174.90. MS, m/z (%): 1038 (M+, 2), 1021 (4), 1006
(15), 237 (25), 182 (75), 162 (10), 112 (20), 92 (55), 59 (72), 43 (100).
Macrocyclic octaamide tetraimide 11. IR (KBr, cm-1): ν 3862-3578 (NH), 1665-1668 (C=O). 1H-NMR
(DMSO-d6): δ 1.38-1.90 (m, 12H, 4CH3), 3.65-3.72 (m, 4H, 4CH), 8.05-7.75 (m, 8H, Ar-H), 8.23-8.35
(m, 6H, 2 pyrid-H), 9.85, 10.15 (2s, 8H, 8NH exchangeable with D2O). 13C NMR: 17.95, 51.15,
119.68, 123.45, 134.75, 138.23, 138.78, 148.75, 157.86, 160.05, 172.18. MS, m/z (%): 1138 (M+, 2),
1124 (4), 1067 (15), 863 (12), 569 (8), 295 (10), 275 (100), 204 (75), 133 (35), 59 (78).
4. Conclusions
A series of chiral linear and macrocyclic bridged pyridines has been prepared starting from
pyridine-2,6-dicarbonyl dichloride (2). The structure assignments of the new compounds are based on
chemical and spectroscopic evidence. The newly synthesized compounds 3-11 have been screened for
their bactericidal and fungicidal activities. Among them compounds 5, 6, 7, 9, 10 and 11 have
antimicrobial activities higher than that of the other prepared compounds. On the other hand,
compounds 3, 5, 7, 9, 10 and 11 also exhibited interesting high antifungal activities in addition to their
antibacterial activities. Ciprofloxacin and ketaconazole were used as antibacterial and antifungal
reference drugs, respectively.

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Acknowledgements
The financial support of the Research Center of the College of Pharmacy, King Saud University is
greatly appreciated. The kind help of El-Sayed E. Mostafa, Department of Microbial Chemistry,
National Research Center, Cairo, Egypt, for carrying out the antimicrobial screening is
highly appreciated.
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Sample Availability: Samples of the compounds are available from the authors.
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