Click reaction based synthesis, antimicrobial, and cytotoxic activities of new 1,2,3-triazoles

Article abstract of DOI:10.1016/j.bmcl.2015.04.096

Three-motif pharmacophoric models 20a-e and 21-25 were prepared in good yields by CuAAC of two azido substrates 2 and 11 with seven terminal acetylenic derivatives including chalcones 17a-e, theophylline 18 and cholesterol 19. The structure of these compounds was elucidated by NMR, MS, IR spectroscopy and micro analyses. This series was screened as antimicrobial and cytotoxic agents in vitro. Most derivatives showed appreciable antibacterial activity, but they displayed weak cytotoxic, and antifungal activities. Notably, conjugate 25 (cream of the crop) was found to be more active than Ampicillin against Escherichia coli and Staphylococcus aureus and showed appreciable antifungal and cytotoxic activities as well.

Full text of DOI:10.1016/j.bmcl.2015.04.096

Accepted Manuscript
Click reaction based synthesis, antimicrobial, and cytotoxic activities of new
1,2,3-triazoles
Mohamed Ramadan El Sayed Aly, Hosam Ali Saad, Moselhy Abdel Naby
Moselhy Mohamed
PII:
S0960-894X(15)00440-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.04.096
BMCL 22680
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 March 2015
25 April 2015
30 April 2015
Please cite this article as: Aly, M.R.E., Saad, H.A., Mohamed, M.A.N., Click reaction based synthesis, antimicrobial,
and cytotoxic activities of new 1,2,3-triazoles, Bioorganic & Medicinal Chemistry Letters (2015), doi: http://
dx.doi.org/10.1016/j.bmcl.2015.04.096
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Click reaction based synthesis, antimicrobial, and cytotoxic activities of new
1,2,3-triazoles
Mohamed Ramadan El Sayed Aly a,b,*, Hosam Ali Saad a,c, Moselhy Abdel Naby Moselhy
Mohamed a,d
a Chemistry Department, Faculty of Science, Taif University, Hawyah-Taif, Kingdom of Saudi Arabia;
b Chemistry Department, faculty of Applied Science, Port Said University, 42522-Port Said, Egypt.
c Chemistry Department, faculty of Science, Zagazig University, Zagazig, 44511, Egypt.
d Chemistry Department, faculty of Science, Cairo University, Cairo, Egypt.
ABSTRACT
Three−motif pharmacophoric models 20a−e and 21−25 were prepared in good yields by CuAAC of two azido
substrates 2 and 11 with seven terminal acetylenic derivatives including chalcones 17a−e, theophylline 18 and
cholesterol 19. The structure of these compounds was elucidated by NMR, MS, IR spectroscopy and micro analyses.
This series was screened as antimicrobial and cytotoxic agents in vitro. Most derivatives showed appreciable
antibacterial activity, but they displayed weak cytotoxic, and antifungal activities. Notably, conjugate 25 (cream of
the crop) was found to be more active than Ampicillin against E.coli and S. aureus and showed appreciable
antifungal and cytotoxic activities as well.
Keywords: Click reaction; Quinoline; Chalcone; Cholesterol; Theophylline; Biological activity
*
Corresponding author Tel.: +966 (0)56 269 4753; +20 (0)100 507 3049.
E-mail address: mrea34@hotmail.com (M.R.E. Aly).
Abbreviations: (CuAAC), copper catalyzed azide−alkyne cycloaddition; (RuAAC), Ruthenium II catalyzed
azide−alkyne cycloaddition; HMBC, Heteronuclear multiple bond correlation; (HDACIs), histone deacetylase;
p−TsOH, p−toluenesulphonic acid; (SRB), sulforhodamine B; E.coli, Escherichia coli; S. aureus, Staphylococcus
aureus; A. flavus, Aspergillus flavus; Candida albicans, C. albicans; PZQ, Praziquantel; Dox, Doxorubicin; ELISA,
enzyme−linked immunosorbent assay; ANOVA, analysis of variance.
1

1,3-Dipolar azide-alkyne [3+2] cycloaddition Scheme 1 is a major synthetic approach for
1,2,3-triazoles. Originally, the thermal Husigen cycloadditions are conflicted with simple
reaction conditions and stereospecificity due to formation of both 1,4- and 1,5-disubstituted-
1,2,3-triazoles, therefore, it is confined to symmetrical alkynes.1 Mock et al. demonstrated the
regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles by cycloadditions catalyzed by
amines encapsulated with cucurbituril2 In a breakthrough, Sharpless3 and Meldal4 independently
disclosed the CuAAC for exclusive formation of the 1,4-disubstituted-1,2,3-triazoles giving rise
to a new era for Click-Chemistry. The orientation in disubstituted triazoles was recently studied
and distinguished by 1H−15N HMBC.5
******************************
Scheme 1. Conditions−based regioselectivity of Azide−Alkyne cyclocondensation.
Cu (I) salts were generally used as catalyst in the CuAAC in the presence of a base as
stabilizer and to assist in the ionization of the terminal acetylene. However, in situ generation of
Cu (I) salts from Cu(II)SO4 reduced by sodium ascorbate without the need for a base was more
convenient and more commonly used procedure. The reaction was well performed at low
temperatures or even at ambient conditions in aqueous or polar solvents like THF and DMF.
However, acetonitrile was avoided for its tendency to coordinate with Cu(I) salts, furthermore,
halogenated solvents were not recommended.6 Epoxides in the presence of NaN3 and acetylenes
could be used as three component system to perform the reaction.7 Fused tetrazoles were also
used as azide surrogates in Click reactions.8 Certain azide substrates such as 2-
azidomethylquinolines were able to be clicked with terminal alkynes in alcohols and in absence
of a reducing agent due to intramolecular chelation−assisted cycloadditions.9 Fokin et al. found
that ruthenium II catalysts gave solely the 1,5-disubstituted triazoles (RuAAC).10
The easiness of the CuAAC, high yield, regioselectivity and specificity without environmental
constraints made it indispensible and evolutionary synthetic tool in chemical research fields.
These fields included polymer chemistry, electrode surfaces, gold surfaces, nanoparticles,
nanotubes, silica particles, porous beads, magnetic metal oxides, microcontact printing, corrosion
2

retardants, optical brighteners, light stabilizers, fluorescent whiteners,11−19 and development of
sensors for detection of metal ions.20
In biochemistry, the reaction could be performed on cellular scale to modify biomolecules and
cell surfaces for imaging purposes and functioning for physiological investigations.21−24
In pharmacology, formidable designs endowed with plethora of biological significances are
constantly appearing by clicking assorted azide and terminal acetylenic structure motifs to
discover new leads. Theses designs included activities as antibacterial,25−27 for example
Tozabactam is a commercial triazole based β−lactamase inhibitor,28,29 antifungal,30 and
antiviral31 including multidrug−resistant HIV−1 protease variants.32 Clicked triazoles were
reported as anti−leishmanial,33 anti−Trypanosoma crusi,34 and antimalarial35 too. Many reports
presented their activities as anti human carbonic anhydrase,36 Pim kinases37 and histone
deacetylase (HDACIs)38,39 with concurrent potential antiproliferative, anti−inflammatory and
cognition−enhancing activities. Furthermore, several 1,2,3-triazoles were active as antiallergic,
antiepileptic7 and epigenetic modulators of gene transcription.39 The pharmacological
significances of 1,2,3-triazoles were reviewed40,41 and a computer algorithm called,
AutoClickChem, was capable of performing many Click−reactions in Silico to produce large
combinatorial libraries of compound models for use in virtual screens.42
This piece of work describes the synthesis of ten 1,4-disubstituted-1,2,3-triazoles as three-
motif pharmacophoric derivatives based on CuAAC of chloroquinoline and glucose azide
substrates with a set of terminal acetylenes including chalcones, theophylline and cholesterol.
While, chloroquinolines are wide spectrum pharmacophores,43 glucose was selected as surface
recognition tag.38 Time since, chalcones44 and theophylline45 are well documented for their
diverse pharmacological profiles. Recently, cholesterol derivatives are progressively emerging as
pharmacologically giant targets. Cholesterol can be functionalized at the double bond and the 3-
β-OH group as well, to afford quite effective antimicrobial and cytotoxic probes. An explanation
for this potency is attributed to the propensity of bacteria46,47 and cancerous cells to elevate
serum cholesterol level.48 While, bacteria do so to incorporate it in its own membrane to acquire
resistance against the human immune defense and antibiotics,46 cancerous cells use it to build
membranes of new cells.48 This feature was exploited to develop cholesterol based antimicrobial
agents,49 besides drug carriers50 and antiproliferative agents51 in cancer research. Also,
3

cholesterol-peptide conjugates were reported as effective antiviral agents,52 while cholesterol
metal complexes were reviewed for their rule in managing Alzheimer`s disease53 and cholesterol
glycosides displayed immunostimulant activities.54 Thus, the confluence of these activities
prompted us to merge cholesterol in part of the target architectures through propargylation of the
3-OH group as it is compatible with our strategy that depended on CuAAC. The antimicrobial
and cytotoxic activities of these architectures in vitro were screened to discover the optimum
combination as a new lead structure for prospective investigations.
Azidolysis of chloroquinoline derivative 155 Scheme 2 with NaN3 in hot DMF afforded 2 in
very good yield as the first substrate for CuAAC. To prepare the second substrate 11,
commercially available spacer−linker azidohexanol 8 was prepared from diol 3 or aminohexanol
4. Thus, selective monobromination of 3 ensued by 0.5 equivalents of CBr4/PPh3 or tosylation in
the presence of 0.75 equivalents of p−TsCl in Et3N, added in portions, afforded 5 and 6 in
moderate yields, respectively. Azidolysis of both 5 and 6 under the same conditions for 1
afforded 8 in excellent yields. Azide 8 was also prepared from 4 according to the diazo−transfer
1
procedure in high yield.56 IR and H NMR spectra of 8 were in agreement with the reported
1
data.57 On the other hand, azidolysis of 6−chloro−1−hexanol was incomplete, as shown by H
NMR even after prolonged reaction times. The conversion in this case also was conflicted by
difficult purification due to polarity resemblance between the substrate and 8. This problem was′t
encountered in the case of azidolysis of both 5 and 6.
Coupling of glycosyl acceptor 8 with donor 958 that is anomerically activated by the
trichloroacetimidate as leaving group in the presence of TMSOTf as promotor afforded the
expected pure β−glycoside 10 in 70% yield. A high J1,2 7.8 Hz value at δ 4.49 ppm precluded
compound 10 to be an α−anomer since such glycosides have J1,2 values less than 5.0 Hz.
Saponification of 10 under the mild transesterification conditions of Zémplen59 yielded the target
second azide substrate 11 in low yield. All of the previous azides showed the diagnostic medium
N3 stretching vibration band at 2100 cm−1.
4

***************************************
Scheme 2. Reagents and conditions: (a) NaN3, DMF, 90−100 °C [(2, 73%); (5→8, 90%); (6→8, 85%)]; (b)
CBr4/PPh3, DCM−THF (55%); (c) p−TsCl (0.75 eq), Et3N, THF (6, 47%, 7, 53%); (d) Tf2O, NaN3, CuSO4.5H2O,
NaHCO3 (90%); (e) TMSOTf (0.02 eq), DCM, rt (98%); (f) NaOMe/MeOH (31%).
Seven terminal alkynes 17a−e, 18 and 19 Scheme 3 were prepared as complement for azides 2
and 11 to ensue variations of CuAAC reactions. Phenolic chalcones 13a,b,d,e60−62 and
theophylline 14 were propargylated by stirring with propargyl bromide in DMF at ambient
temperature in the presence of K2CO3 to afford 17a,b,d,e and 18 in acceptable yields. To prepare
17c, compound 12 was propargylated as previously described to afford intermediate 16 followed
by condensation with p−dimethylaminobenzaldehyde under Claisen−Schmidt conditions. This
procedure was used to avoid quenching of propargyl bromide as quaternary ammonium salt by
the dimethylamino group if the relevant phenolic chalcone was propargylated as described for
17a,b,d,e. Cholesterol 15 was propargylated by propargyl bromide in DMF−Et2O at its
secondary OH group in the presence of NaH to afford 19 in excellent yield.
**********************************
Scheme 3. Reagents and conditions: (a) Propargyl bromide, K2CO3, DMF, rt [16 (47%); 17a (R = Ph, 95%); 17b (R
= p-MeOPh, qu); 17d (R = 2-Furanyl, 53%); 17e (R = 2-Thiofuranyl, 58%); 18 (78%)]; (b) NaH, DMF−Et2O (19,
93%); (c) p-dimethylaminobenzaldehyde, NaOH, EtOH, rt (17c, R = p-dimethylaminophenyl, 97%).
The IR spectra of these acetylenes displayed strong ≡C−H and weak C≡C stretching vibration
bands at ~ 3220 and 2110 cm−1, respectively. The shielded ≡C−H signal, 1H NMR, was observed
at ~ 2.56 ppm as doublet due to extended weak coupling, J 2.4 Hz, with the methylene protons
which appeared at ~ 4.77 ppm.
The first target 1,2,3-triazole architectures 20a−e, 21 and 22 Scheme 4 in this study were
prepared by clicking azidoquinoline 2 with propargylated chalcones 17a−e, theophylline 18 and
cholesterol 19. Structurally, these 1,2,3-triazoles have chloroquinoline as permanent arm at N1
and the basic skeleton of 17a−e, 18 and 19 as variable motifs at C−4. The reactions proceeded
properly in short time in the presence of a catalytic amount of CuSO4.5H2O reduced in situ by
5

L−ascorbic acid. THF−H2O combination was a good solvent mixture to bring all components
into solution. No reaction was observed if H2O was not added since the copper salt was out of
the solution phase. Yields were generally high upon smooth work up and chromatographic
purification by virtue of the high polarity of the resulting triazoles compared with 2 and the
propargyl substrates 17a−e, 18 and 19.
********************************
Scheme 4. Reagents and conditions: (a) 17−19, CuSO4. 5H2O, L-Ascorbic acid, THF−H2O 4:1, rfx. [20a, R = Ph
(92%); 20b, R = p-C6H4-OMe (73%); 20c, R = p-C6H4-NMe2 (61%); 20d, R = Furan-2-yl (87%); 20e, R =
Thiophen-2-yl, (63%); 21 (75%); 22 (76%)].
The strong ≡C−H and weak C≡C stretching vibration bands disappeared in these triazoles and
1
the ≡C−H H NMR signal as well. The OCH2 protons of the parent propargyl group that
positioned at C−4 of the clicked triazole rings was shifted downfield to δ ~ 5.5 ppm in most
cases due to the magnetic anisotropic effect of the triazole ring and appeared as singlet. The
enone moieties in 20a−e retained their red shift for the C=O stretching vibration bands at ~ 1640
cm−1 and high vicinal JH,H values of ~ 15.6 Hz corresponding to their s−trans configuration.
However, chalcones 17a, 20b and 20d are existing as s−cis / s−trans mixtures since they
1
displayed a second C=Ostr band at ~1710 cm−1. The disappearance of the acetylenic IR and H
NMR spectroscopic features precluded the possibility of azide−alkene cyclocondensation at the
enone moiety which was reported under tetrabutyammonium hydrogensulfate catalysis in
absence of terminal acetylenic groups.63 Theophylline modified triazole 21 showed two C=O
stretching vibrations at 1653 and 1696 cm−1 for the conjugated C=O at position 6 and that at
1
position 2, respectively. Cholesterolyl triazole 22 showed the fingerprint H NMR signals of
cholesterol at δ 5.4 ppm for C−6, 3.45 ppm for C−3, while, all CH3 residues appeared with their
expected multiplicities and they were well resolved within the chemical shift range δ 1.03−0.68
ppm. Exceptionally, the triazole C−4 methylene group retained the chemical shift value of the
parent alkyne 19.
6

The second set of triazoles Scheme 5 embraced three triazoles having a fixed
β−hexylglucpyranoside arm at N1 and a variety of motifs at C−4 including a chalcone 23,
theophylline 24 and cholesterol 25. Structurally, this set included the following essential
pharmacophoric motifs, glucose as surface recognition cap, a six−carbon arm as recommended
spacer for efficient recognition and a bifunctional pharmacophore Figure 1. Glucose, as ligand
for lectins, act as homing cap for the terminal pharmacophore at cellular surfaces to augment the
potential of their activities.38
****************************
Figure 1. Schematic representation of the three−motif pharmacophoric design of compounds 23-25.
Reactions were easily performed by clicking 11 with the relevant alkynes 17c, 18 and 19
exactly as described for the synthesis of 20a-e, 21 and 22. They were purified by simple flash
chromatography using nonhalogenated solvent mixtures. Yields were a little low in the case of
23 and 24, while, 25 was obtained in high yield.
**********************************
Scheme 5. Reagents and conditions: (a) 17d, 18 or 19, CuSO4. 5H2O, L-Ascorbic acid, THF-H2O 4:1, rfx. [23 (44%
from 17d); 24 (36% from 18); 25 (78% from 19)].
1
The H NMR spectra of these triazoles showed clearly the signals of the sugar moiety in all
triazoles and the hexyl arm in the case of 23 and 24, while, it was overlapped with the cholesterol
protons in 25. Compound 25 afforded confirmation of the trazoleˊs H−5 chemical shift at δ 7.94
ppm. All intermediates and target triazoles synthesized in this series showed molecular ion peaks
at different intensities by EI−MS. Fortunately, the three glucose containing triazoles 23−25
afforded their molecular ion peaks under this harsh ionization conditions. Finally, 25 could be
obtained by CuAAC of 10 and 19 followed by deacetylation in better yield compared with the
coupling of 11 with 19.
The antimicrobial activity of the ten target triazoles 20a−e and 21−25 was tested in vitro
against four microorganisms namely Escherichia. coli ATCC 11775, Staphylococcus. aureus
7

ATTC 12600, Aspergillus flavus Link and Candida. albicans ATCC 7102. Screening was done
according to the Kirby−Bauer disc diffusion method.64 Structurally, these triazoles were divided
into two groups according to their triazole`s N1 domain. Group A comprised a common
quinoline domain 20a−e, 21 and 22, while group B had a common glucopyranosylhexyl domain
23−25. In both groups, there were variations, such as, chalcones, theophylline and cholesterol as
triazole`s C4 substituents. Inhibition zone diameters were calculated and compared with the
control; Ampicillin in case of bacteria and Amphoterecin B in case of fungi Figure 2.
***************************************
Figure 2. In vitro antimicrobial activity of compounds 20a−e and 21−25 against E.coli, S. aureus. A. flavus and C.
albicans. Ampicillin was used as positive control in case of E. coil and S. aureus, while, Amphotericin B was used
in case of A. flavus and C. albicans. Different letters on the column for each parameter varied significantly at p ≤
0.05.
As shown in Figure 2, all triazoles were active against E. coli and varied significantly with the
control. Compound 25 from group B was the unique to cross the activity of the control by 18%.
In the same group, compounds 23 and 24 were equally 59% less active than the control reflecting
the preference of the cholesterolyl ring over the chalcone and theophylline moieties in
developing the activity of this pharmacophoric model. In group A compounds, chalcone 20b
showed an activity of 9% less than the control but putting it in front of the seven triazoles in this
group and giving a preference for the methoxy substituent on Ring B of the chalcone entity.
Chalcones 20a,c,e were varied significantly with the control but varied insignificantly with each
other and they were 18, 23 and 32% less active than Ampicillin, respectively. Triazole 21 from
group A varied significantly with the control and it was 41% less active than the control.
Derivatives 22, 23 and 24 varied significantly with the control without significant variations with
each other. Theophylline containing triazole 22 was 45 % less active than Ampicillin, Thus, the
impact of the theophylline moiety in 21 and 24 was weak against this bacterial strain.
In case of S. aureus, compound 25 also showed the best activity among the ten triazoles. It
varied significantly compared with the control and it was 55% more active than it. Triazoles
20b,c,e, 21, 22 and 23 varied insignificantly with the control. Derivatives 20a and 24 varied
8

significantly with the control and they were the least active triazoles (55%). They varied
insignificantly with each other. Compound 20d was the unique inactive triazole and comparing
the structure of 20d with 20e denotes to the impact of the sulfur atom of the thiofuranyl moiety
in case of 20e over the oxygen atom of the furanyl entity in 20d on its activity toward this
bacterial strain. This structural variation was the unique difference between them.
Concerning the tested fungi, only 20b and 25 showed antifungal activity against A. flavus.
They varied significantly with the control and with each other. Compound 25 was 12% less
active than the control, while 20b was less active by 41%.
On the other hand, triazole derivatives 20a,b, 22, 23 and 25 showed antifungal activity against
C. albicans and varied significantly with the control. Compound 25 from group B was the most
active derivative, 12% less active than the control. Other triazoles varied insignificantly with
each other and they were 30−47% less active than the control.
As the promising and most active triazole in this consideration, the antimicrobial activity of
25 was further quantified as MIC90 values65 and compared with the controls.
The compound recorded an MIC90 value of 122 mM against E.coli compared with a value of
162 mM for Ampicillin, i.e. it was 25% more active than the control. Also, its MIC90 value was
94 mM against S. aureus, thus, it was 52% more active than the control that recorded a value of
194 mM.
In case of fungi, this triazole was less active than the control; it showed against A. flavus an
MIC90 value of 268 mM compared with 228 mM for Amphoterecin B. Thus, it was about 18%
less active than the control, relatively as in case of C. albicans, where it gave a value of 239 mM
compared with a value of 198 mM for Amphoterecin B.
In conclusion, these results were compatible with the inhibition zone diameter results and
demonstrated clearly the value of 1,2,3-triazoles decoration with the glucopyranosylhexyl and
cholesteroyl moieties to develop the antimicrobial activities of 25 which emerged from this study
as the most promising triazole of reproducible antimicrobial activity.
9

Target triazoles 20a−e and 21−25 were screened in vitro as cytotoxic agents against human
prostate cancer cell line PC3 using sulforhodamine B colorimetric (SRB) assay and doxorubicin
as positive control.66
*********************************
Figure 3. Cytotoxicity effect of compounds 20a−e and 21−25 on PC3 cell line. Doxorubicin (Dox) was used as
positive control. Different letters on the column varied significantly at p ≤ 0.05.
As shown in Figure 3, all derivatives showed different levels of cytotoxicity against prostate
cancer PC3 cell line and they were varied significantly with their control (Doxorubicin). The best
activity was observed for cholesterol derivative 25 from group B which was 2.3−fold less active
than the control. The activity of 23 that retain glucose as surface recognition tag and a chalcone
terminal instead of cholesterol was 3.6−fold less active than the control and nearly twice less
active than 25.
Theophylline containing triazole 24 was the least active probe in this consideration, 8−fold
less active than the control. On the other side, compounds 20a,d from group A were 3−fold and
3.1−fold less active than the control, respectively. Despite, they varied insignificantly with 25.
Chalcones 20b,c,e varied insignificantly with each other but they varied significantly with
chalcones 20a,d and were less active than them.
Both compounds 21 and 22 were 5.4 and 5.3−folds less active than the control, respectively.
In conclusion, theophylline had low impact on developing cytotoxic effects, while, merging of
cholesterol with glucose as in compound 25 gave better cytotoxicity over merging with quinoline
as in compound 22. It might be deduced from this structure activity relationship that, clicking of
more propargylated chalcone derivatives either with azidoquinoline or azidoglucose might lead
to more potential cyctotoxic probes. Also, substitution of D-glucopyranose in 25 by other
glycans might lead to more promising antimicrobial and cyctotoxic effects.
In conclusion, a set of three−motif pharmacophoric probs 20a−e and 21−25 was prepared by
CuAAC of relevant propargyl chalcones, theophylline or cholesterol with azidoquinoline or
glucopyranosylhexyl azide. This set was screened as antimicrobial, and cytotoxic agents in vitro.
10

Triazole 25 showed moderate antifungal activity against A. flavus and C. albicans, while it was
more active than Ampicillin against E. coli and S. aureus. Also, compound 25 showed the best
cytotoxic activity against prostate cancer PC3 cell line in vitro. These results gave evidences for
the value of tagging triazolylcholesterol with glucose, as surface recognition tag, in developing
new probes of potential pharmacologic activities. Assuming that 25 is a new antibacterial lead
structure encouraged us to substitute glucose with chitobiose, in a progressing work, for potential
targeting of E. coli K1. This strain is the causative agent of bacterial meningitis. Further
modifications of cholesterol are going in due course as well.
Acknowledgments
The financial support of Port Said and Taif Universities, Grant Number 1−434−2401 are
gratefully acknowledged.
Supplementary data
Supplementary data related to this article can be found at
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15

Scheme 1.
16

Cl
Cl
Cl
4: R = NH2
O
H
R
b
N
1
3:
R = OH
d
O
c
H
R
a
5: R = Br
O
Ts
O
Ts
O
N3
+
Ts
H
O
a
6
7
N
a
2
O
H
N3
8
OAc
O
AcO
AcO
O
CCl3
NH
e
OAc
9
OAc
O
AcO
O
AcO
N3
OAc
10
f
OH
O
HO
HO
O
N3
OH
11
Scheme 2.
17

Scheme 3.
18

Scheme 4.
19

OH
O
HO
HO
O
N3
OH
11
a
OH
O
HO
HO
O
O
N
N
OH
N
O
O
23
O
N
N
OH
O
O
N
HO
HO
O
N
N
N
OH
N
24
OH
HO
HO
O
O
OH
N N
H
N
H
H
O
25
Scheme 5.
20

Captions List
Scheme 1/Captions .................................................... Page 2
Scheme 2/Captions .................................................... Page 5
Scheme 3/Captions .................................................... Page 5
Scheme 4/Captions .................................................... Page 6
Scheme 5/Captions ……………………………………. Page 7
Fig. 1/Captions
Fig. 2/Captions
Fig. 3/Captions
.................................................... Page 7
.................................................... Page 8
..................................................... Page 10
21

Figure 1.
22

Figure 2.
23

Figure 3.
24

Surface
Recognition
Tag
Hexyl Spacer
Bifunctional
Pharmacophore
Surface Lectin
Cell
Glu
MIC90 (mM)
E. coli: 122/162 (Ampicilin)
S. aureus: 94/194 (Ampicilin)
OH
O
A. flavus: 268/226 (Amphotericin B)
: 236/198 (Amphotericin B)
HO
HO
.
O
H
OH
N
N
Prostate cancer PC3 cell line (IC50 M):
19.7/8.6 (Doxorubicin)
N
H
H
O
25