Antiinflammatory and Antiproliferative Activity of Naphthoxazole, Fused Hetero-benzoxazole and Bridged Benzobicyclic Photoproducts

Article abstract of DOI:10.5562/cca3530

Biological activity of naphthoxazoles, fused hetero-benzoxazoles and benzobicyclo[3.2.1]-derivatives was investigated in proliferation and inflammation based assays. The tested compounds were prepared by photocylization or photocycloaddition reactions. Effect of compounds on proliferation of several cancer cell lines was determined by measuring cell metabolic activity through time. Lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells (PBMC) was used to investigate antiinflammatory properties of the compounds. Several naphthoxazoles and fused hetero-benzoxazoles inhibited TNFα protein expression in LPS stimulated PBMC, indicating possible antiinflammatory role which would be interesting to further investigate. Physico-chemical properties of tested compounds have been also studied using chromatographic lipophilicity measure, chrom logD and logP was calculated as the importance of physico-chemical properties of compounds at early stage of discovery of new drugs is well established. The similarities in structure and activity of some representative compounds affirm the need to further address their antiinflammatory properties.

Full text of DOI:10.5562/cca3530

O R I G I NA L S C I E N T I F I C P A P E R
Croat. Chem. Acta 2019, 92(2)
Published online: October 14, 2019
DOI: 10.5562/cca3530
Antiinflammatory and Antiproliferative Activity of
Naphthoxazole, Fused Hetero-benzoxazole and
Bridged Benzobicyclic Photoproducts
Ivana Šagud,1 Ana Ratković,1 Matea Cedilak,2 Ivo Zlatar,2 Martina Bosnar,2,* Vanja Kelava,3 Irena Škorić1,*
1
2
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia
Pharmacology in vitro, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia
3
Drug metabolism and Pharmacokinetics, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia
Authors’ e-mail addresses: Martina.Bosnar@glpg.com; iskoric@fkit.hr
RECEIVED: May 21, 2019
REVISED: July 19, 2019
ACCEPTED: July 21, 2019
TH
THIS PAPER IS DEDICATED TO PROFESSOR KATA MLINARIĆ-MAJERSKI ON THE OCCASION OF HER 70 BIRTHDAY
Abstract: Biological activity of naphthoxazoles, fused hetero-benzoxazoles and benzobicyclo[3.2.1]-derivatives was investigated in proliferation
and inflammation based assays. The tested compounds were prepared by photocylization or photocycloaddition reactions. Effectof compounds
on proliferation of several cancer cell lines was determined by measuring cell metabolic activity through time. Lipopolysaccharide (LPS)
stimulation of peripheral blood mononuclear cells (PBMC) was used to investigate antiinflammatory properties of the compounds. Several
naphthoxazoles and fused hetero-benzoxazoles inhibited TNFα protein expression in LPS stimulated PBMC, indicating possible
antiinflammatory role which would be interesting to further investigate. Physico-chemical properties of tested compounds have been also
studied using chromatographic lipophilicity measure, chrom logD and logP was calculated as the importance of physico-chemical properties of
compounds at early stage of discovery of new drugs is well established. The similarities in structure and activity of some representative
compounds affirm the need to further address their antiinflammatory properties.
Keywords: antiinflammatory activity, antiproliferative activity, benzobicyclo[3.2.1]octadiene, biological activity, hetero-benzoxazole,
naphthoxazole, physico-chemical properties.
synthesis of many biologically active molecules. Some of
the fused polycyclic compounds with the oxazole ring have
INTRODUCTION
ETEROCYCLIC compounds are the most widely used
class in pharmaceutical and agrochemical industries.
shown antibacterial and antituberculosis[8] activities as well
as anticancer activitiy[9] and some have been tested for
antioxidant activity.[10] Compounds with the bicyclo[3.2.1]-
skeleton are potent inhibitors of dopamine and serotonin
transporters and they have crutial role in treatment of
central nervous system (CNS) and Alzheimer’s disorders.[11]
In our group, a whole library of both groups of these
polycylic compounds was obtained by utilization of the
photochemical synthesis.[12–16] Naphthoxazoles as a group
of compounds have been known since Fisher synthesized 2-
methylnaphtho[1,2-d]oxazole and 2-methylnaphtho[2,1-
d]oxazoles in 1906.[17] In the following years many synthetic
approaches were developed for the synthesis of these
compounds.[18] The synthesis of naphthoxazoles[19] and
H
They exhibit numerous biological activities, among which are
antibacterial, antifungal, antiviral, antiinflammatory, antide-
pressant etc.[1] For example, pyrazolone derivatives, phena-
zone, metamizole, aminophenazone, phenyl buta-zone and
apazone are non-steroidal antiinflammatory drugs (NSAID)
that exhibit antiinflammatory, analgesic and antipyretic acti-
vity due to inhibition of cyclooxygenase (COX) enzymes.[2] Pu-
rine analogues, pyrimidine analogues and antifolates are cy-
tostatic compounds that inhibit cell proliferation and are used
in cancer treatment, as well as for autoimmune disorders.[3–5]
In general the oxazole moiety[6] and the bicy-
clo[3.2.1]-core[7] are important building blocks for the
This work is licensed under a Creative Commons Attribution 4.0 International License.

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I. ŠAGUD et al.: Antiinflammatory and Antiproliferative Activity of Photoproducts
N
O
very good yields. The required styryloxazoles were synthe-
O
N
sized in one step by Van Leusen reaction from aryl / he-
teroaryl substituted α,β-unsaturated aldehydes and tosyl-
methyl isocynide (TosMIC). In the case of synthesis of 2/3-
thienylethenyl- and 2/3/4-pyridylethenyloxazoles the nece-
ssary unsaturated aldehydes were prepared by Wittig reac-
tion from the corresponding aldehydes and formylme-
thylenetriphenylphosphorane.
Het/Ar
Het/Ar
Het
Het/Ar
Chrom logD Determination
Figure 1. General structures of the investigated compounds.
Chrom logD values were determined from the following
equation: chrom logD = 0.0857 × CHI – 2 (ref.
Chromatographic Hydrophobic Index (CHI) values have
been determined from gradient retention times (tR) as
described by Valkó and Slegel.[41,42] These values
approximately correspond to the volume percentage of
organic component in the mobile phase when the
compound elutes. CHI values were determined at pH 7.4.
Chromatograms were obtained using an Agilent 1100
Series HPLC instruments equipped with diode array
detector (DAD) coupled with Micromass Quattro API mass
spectrometer. Data acquisition and processing were
performed with MassLynx software version 4.1. The
column used for CHI determination was Luna C18 (50mm ×
3 mm i.d., 5 µm particle size, 100 Å). The aqueous part of
the mobile phase was 50mM ammonium acetate adjusted
with ammonia solution to pH 7.4. As an organic part of their
mobile phase acetonitrile was used. The mobile phase flow
rate was 1 mL min–1 for all measurements. The gradient
retention times tR were measured under the following
gradient condition: 0 to 3 min linear gradient from 0 to 100
% acetonitrile; 3 to 3.5 min 100 % acetonitrile; 3.5 to 3.7
min from 100 to 0 % acetonitrile; and 3.7 to 5 min re-
equilibration time with 100 % of aqueous part of the mobile
phase.
fused hetero-benzoxazoles[19,20] (Figure 1) in one photo-
cyclization step by utilising light as a very clean reagent
gave a new and easy path to this kind of polycyclic systems
that are taxing to obtain via ground state organic synthesis.
Syntheses of compounds containing bicy-clo[3.2.l]octane
and bicyclo[3.2.l]octadiene core (Figure 1) are also
documented in the literature.[21] Bicyclo[3.2.l]-skeleton can
be constructed using different synthetic pathways, one of
which is the photochemical cycloaddition approach that
has been developed by our group in batch and flow
photochemical reactor.[22–34]
Guided by all above mentioned compounds, we have
selected 32 compounds from both types of photoproducts
and investigated their biological activity in proliferation and
inflammation based assays. Effect of compounds on
proliferation of several cancer cell lines was determined by
measuring cell metabolic activity through time. On the
other hand, lipopolysaccharide (LPS) stimulation of
peripheral blood mononuclear cells (PBMC) was used to
investigate antiinflammatory properties of the compounds.
Physico-chemical properties of tested compounds
have been studied using chromatographic lipophilicity
measure, chrom logD and logP was calculated. The
importance of physico-chemical properties of compounds
at early stage of discovery of new drugs is now well
established.[35–37] Lipophilicity measurements by reverse
phase chromatography have been already proven as fast
and efficient method for compound profiling in the early
phase of optimization and results are expressed as
Chromatographic logD (chrom logD).[38–40] In this paper we
analysed also the physico-chemical properties of the tested
compounds as possible reason for their biological activity.
Biological Activity
Effect of compounds on cell proliferation was determined
in cancer cell lines THP-1, Jurkat and HL-60. The assay is
based on ability of metabolically active cells to convert MTS
tetrazolium compound to formazan product detectable by
absorbance at 490 nm. The quantity of formazan product is
proportional to the number of metabolically active cells. In
this assay staurosporine was used as reference compound
since it is a protein kinases inhibitor which induces
apoptosis. Furthermore, antiinflammatory activity of
compounds was determined in LPS stimulated PBMC assay.
LPS is one of the components of Gram-negative bacteria
cell wall and is recognized by Toll-like receptor 4 (TLR4). The
activation of TLR4 signaling induces release of cytokines
among which are interleukin-8 (IL-8) and tumor necrosis
factor α (TNFα), therefore leading to inflammatory
response. In this assay, a widely used corticosteroid
EXPERIMENTAL SECTION
Chemistry
Investigated naphthoxazoles, fused hetero-benzoxazoles
and benzobicyclo[3.2.1]-derivatives were previously
synthesized and completely characterized.[14,15,19,20,22] They
were prepared by photocylization or [2+2]-photocyclo-
addition reactions from corresponding starting materials in
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I. ŠAGUD et al.: Antiinflammatory and Antiproliferative Activity of Photoproducts
3
dexamethasone was used as reference compound because
of it’s antiinflammatory activity.
Systems). 1% BSA (Sigma), 5 % sucrose (Kemika) in PBS
(Gibco) was used as blocking buffer, while cell supernatants
were diluted either 4x for TNFα analysis or 150x for IL8
analysis in 1 % BSA in PBS. Furthermore, 250 ng/mL of TNFα
detection antibody (R&D Systems) or 25 ng/mL of IL8
detection antibody (R&D Systems) were used in Elisa assay,
while Chemiluminiscence ELISA Substrate (Roche) was used
for developing the signals. Luminescent signals were
measured using EnVision 2104 Multilabel Reader (Perkin
Elmer).
Cell Culture
Human cell lines THP-1 (TIB-202) and Jurkat (TIB152) were
purchased from ATCC, while human cell line HL-60 (CCL-
240) was purchased from ECACC. All cell lines were
maintained in cell culture in RPMI medium (Lonza)
supplemented with 10 % heat inactivated fetal bovine
serum (FBS) (BioWest) in CO2 incubator (5 % CO2, 95 %
humidity, 37 °C).
Data Analysis
Cell Proliferation Assay
Effect of compounds on proliferation of THP-1, Jurkat and
HL-60 cells was determined using CellTiter 96 Aqueous One
Solution Cell Proliferation Assay (Promega).
Measured absorbance at 490 nm was used to calculate
percentage of cell proliferation for each compound in
comparison to vehicle cells using Micorsoft Excel software
v2013. Concentrations of TNFα and IL8 were calculated by
extrapolation from their standard curves using Micorsoft
Excel software v2013. Obtained concentrations were used
to calculate percentages of inhibition of each compound by
first subtracting average value of vehicle samples from all
other samples. Furthermore, percentage of inhibition was
calculated using formula: (1 − (compound / average of LPS
triggered controls)) × 100.
96-well plates were seeded with 30 000 HL-60, THP-
1 or Jurkat cells per well, followed by addition of three fold
serial dilutions of test compounds using Mosquito
instrument (TTP labtech). Staurosporine (Sigma) was used
as reference compound. Final testing concentrations of test
compounds were 30 µM to 13.72 nM, while of
staurosporine was from 1 µM to 0.46 nM. Vehicle
contained 0.3 % DMSO. Cells treated with compounds or
vehicle were incubated for 24h, 48h and 72h in CO2
incubator (5 % CO2, 95 % humidity, 37 °C) after which
CellTiter 96 Aqueous One Solution Cell Proliferation Assay
substrate was added following manufacturer’s instructions.
After 4h of incubation with the substrate, absorbance at
490 nm was measured using EnVision 2104 instrument
(Perkin Elmer).
In both assays, logarithm of tested compound con-
centration in M was plotted against calculated percentage
of inhibition using GraphPad Prism v7.04 software.
RESULTS AND DISCUSSION
Chemistry
Investigated naphthoxazoles 1–5 and 12–22, fused hetero-
benzoxazoles 6–11 and benzobicyclo[3.2.1]-derivatives 23–
25 and 28–32 (Schemes 1 and 2, Figures 2 and 3) were
previously synthesized and completely characteri-
zed.[14,15,19,20,22] They were prepared by photocylization or
[2+2]-photocycloaddition reaction from the corresponding
starting conjugated compounds in very good yields. The
required styryloxazoles were synthesized in one step
(Scheme 1) by Van Leusen reaction from aryl/heteroaryl
substituted α,β-unsaturated aldehydes and tosylmethyl
LPS Stimulation Assay
Human peripheral blood mononuclear cells (PBMC) were
isolated from healthy volunteer’s blood obtained from the
Croatian Institute for Transfusion Medicine. Blood was
diluted 1:1 with PBS and PBMCs were isolated by
centrifugation in Lymphoprep (Axis-Shield) density
gradient. 96-well plates were seeded with 200 000 PBMCs
per well in RPMI 1640 (Lonza) medium supplemented with
10 % FBS (Sigma). Cells were incubated with three fold
serial dilutions of test compounds for 1h in CO2 incubator
(5 % CO2, 95 % humidity, 37 °C), followed by overnight
stimulation with 1 ng/mL of LPS from E. coli 0111:B4
(Sigma) in CO2 incubator. Final testing concentrations of
test compounds were 30 µM to 13.72 nM. Dexamethasone
was used as reference compound and it was tested from 1
µM to 0.46 nM. 0.3 % DMSO was used as vehicle. After
overnight incubation, concentrations of TNFα and IL8 were
determined in cell supernatants using 384-well format
sandwich Elisa assay. Lumitrac 600 microplates (Greiner)
were coated with 1 µg/mL of TNFα capture antibody (R&D
Systems) or 2.5 µg/mL of IL8 capture antibody (R&D
N
O
ν
h
Het/Ar
TosMIC
Het/Ar
CHO
CHO
Het/Ar
N
I2
O
N
O
Wittig
ν
h
Het/Ar
Het/Ar
Het/Ar
N
reaction
I2
O
N
O
OHC
Wittig
reaction
N
ν
N
O
h
Het/Ar
I2
O
Scheme 1. General scheme for the synthesis of the investi-
gated naphthoxazoles and fused hetero-benzoxazoles.
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I. ŠAGUD et al.: Antiinflammatory and Antiproliferative Activity of Photoproducts
N
N
N
N
N
O
O
O
O
O
O
H3CO
ν
Het/Ar
h
CH3
OCH3
CH3
1
2
3
4
5
Het/Ar
N
N
N
N
N
O
O
O
O
Het/Ar
S
ν
Het
h
N
O
S
N
6
7
8
9
10
CH3
N
O
O
O
O
N
Scheme 2. General schemes for the synthesis of compounds
possessing benzobicyclo[3.2.1]-skeleton.
N
N
N
H
3C
O
N
CH3
CN
CN
11
12
13
14
15
CH3
N
CH3
N
CH3
N
N
dylethenyloxazoles synthesis the necessary unsatu-rated
aldehydes were prepared by Wittig reaction from the
corresponding aldehydes and formylmethylenetriphenyl-
phosphorane.
The investigated benzobycyclic photoproducts 23–
32 were prepared by photocycloaddition of starting
conjugated substrates (photoproducts 23–25 and 28–32,
Figure 3) or by photocyclization reaction (compounds 26
and 27).
O
O
O
O
N
H3CO
H3C
H3CO
H3C
16
17
18
19
N
O
N
O
N
O
F
Cl
20
21
22
Figure 2. Structures of the investigated naphthoxazoles and
fused hetero-benzoxazoles 1–22.
Biology
As it was mentioned before, 32 compounds were selected
belonging to different types of heteropolycyclic photo-
products (Figures 2 and 3) and investigated their biological
activity in proliferation and inflammation based assays
(Figures 4–8). Amongst the tested compounds, naphtha-
isocynide (TosMIC). The investigated hetero-naphthalene
derivatives 26 and 27 are also obtained and isolated as
photocyclization reaction side-products possessing the
potentially interesting structure for biological activity.
In the case of 2/3-thienylethenyl- and 2/3/4-pyri-
H
H
O
O
NH
Ph
N
O
O
O
N
O
Ph
Ph
Ph
23
24
25
26
27
N
S
NH
Ph
OCH3
30
Cl
31
32
29
28
Figure 3. Structures of the investigated benzobycyclic photoproducts 23-32.
Figure 4. Effect of compounds 2, 5, 9 and 11 on proliferation of HL60 cells after 72 h of incubation (n = 3).
Croat. Chem. Acta 2019, 92(2)
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I. ŠAGUD et al.: Antiinflammatory and Antiproliferative Activity of Photoproducts
5
Figure 5. Effect of compounds 2, 5, 9 and 11 on proliferation of Jurkat cells after 72 h of incubation (n = 3).
Figure 6. Effect of compounds 2, 5, 9 and 11 on proliferation of THP1 cells after 72 h of incubation (n = 3).
Figure 7. Effect of compounds 2, 5, 9 and 11 on IL8 production in LPS stimulated PBMC (n = 2).
xazoles 2 and 5, and fused hetero-benzoxazoles 9 and 11
inhibited TNFα protein expression in LPS stimulated PBMC
(Figures 8 and 9), indicating possible antiinflammatory role
which would be interesting to further investigate. On the
contrary, these compounds did not show any effect on IL8
(Figure 7) protein expression, another factor playing
important role in inflammation. Concerning the exact
structure of the tested compounds, naphthoxazoles 2 and
5 possess the methoxy or methyl group in the structure at
the specific positions of different aromatic rings, while
hetero-benzoxazoles 9 and 11 have the condensed pyridine
ring instead of the second aryl moiety. That is very
important to clarify before the study of physico-chemical
properties in general.
Both TNFα and IL8 are mainly produced by
macrophages, they promote inflammation and act as
neutrophil chemoattractants, while TNFα is also one of the
most notable proinflammatory factors in cancer.
Furthermore, related compounds 18, 19 and 20 with similar
structure to compounds 2, 5, 9 and 11 were also tested in
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I. ŠAGUD et al.: Antiinflammatory and Antiproliferative Activity of Photoproducts
Figure 8. Effect of compounds 2, 5, 9 and 11 on TNFα production in LPS stimulated PBMC (n = 2).
(Supplementary figures 4 and 5) . The similarities in
structure and activity of these compounds affirm the need
to further address their antiinflammatory properties. It is
evident that the position on the third (hetero) aromatic ring
is very important for the antiinflammatory properties of the
compounds (Scheme 3). Compounds 2, 18, 19 and 20 have
different substituents on the same position of the con-
densed third aromatic ring, and on the same position
compound 11 possesses the nitrogen atom. On this way the
most important position for the substituents affecting the
antiinflammatory activity is defined including the methoxy,
dimethylamino, chloro substiturnts or the nitrogen atom as
a part of the pyridine moiety (compounds 9 and 11) in the
structure. Also, the methyl substituent on the middle
aromatic ring (compound 5), or between the nitrogen and
oxygen atoms in the oxazole ring (in combination with the
methoxy substituent, compound 18) showed an important
role for the investigated properties.
Figure 9. TNFα expression (pg/mL) in vehicle and LPS (1
ng/mL) stimulated PBMC treated with reference compound
dexamethasone and compounds 2, 5, 9 and 11 (n = 6 for
vehicle and LPS; n = 2 for compound treatments).
The effect of compounds on proliferation of several
cancer cell lines (THP-1, Jurkat and HL-60) was also
investigated. Tested concentrations of compounds did not
exhibit any toxic or antiproliferative activity in these assays,
during 72 h of incubation (Figures 4, 5 and 6). Some inhibi-
LPS stimulated PBMC assay where they achieved up to 40
% of TNFα inhibition and again, no effect on IL8 expression
with nitrogen
methyl substituent
most one
most
one
the
active
the
active
R2
N
N
O
R
O
O
R3
N
Y
R1
Z
methoxy derivative
most one
and
methoxy
-dimethylamino
N,N
most
the
active
ones
the
active
with nitrogen
most
one
active
the
Scheme 3. SAR of naphthoxazole photoproducts concerning antiinflammatory activity.
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7
Figure 10. Effect of reference compound staurosporine on proliferation of HL60 (A), Jurkat (B) and THP1 (C) cells after 72 h of
incubation (n = 3).
tion of proliferation up to 24 % was observed at the highest
concentrations of compounds 9 and 11, however only in
THP1 cells (Figure 6.). Overall, these findings further
support that observed inhibition of TNFα expression is due
to compounds activity, rather than the result of toxicity.
stimulated PBMC were presented and compared to the
effects of the investigated photoproducts. Also, IC50 values
determined for reference compounds in cell proliferation
assay (staurosporine) and LPS stimulation assay (dexame-
thasone) are presented in Table 1.
Reference Compounds
Physico-Chemical Properties
In the investigation of the biological activity of the tested
compounds 1–32, staurosporine and corticosteroid
dexamethasone were used as reference compounds
(Figures 10 and 11). Their effects on proliferation of HL60
(A), Jurkat (B) and THP1 (C) cells after 72 h of incubation
(Figure 10) and on IL8 (A) and TNFα (B) production in LPS
As an initial attempt for better understanding and explan-
ing the biological activity of compounds 1–32, their physi-
co-chemical properties were also investigated. Experimen-
tal lipophilicity, as determined by RP-HPLC was expressed
by using chrom logD. These values were in the range 1.89–
7.50 at pH 7.4. Physico-chemical properties of investigated
Figure 11. Effect of reference compound dexamethasone on IL8 (A) and TNFα (B) production in LPS stimulated PBMC (n = 2).
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I. ŠAGUD et al.: Antiinflammatory and Antiproliferative Activity of Photoproducts
Table 1. IC50 values determined for reference compounds in cell proliferation assay (staurosporine) and LPS stimulation assay
(dexamethasone). N/A = compound not tested.
Compound
IC50 (HL60)
6.4 nM
N/A
IC50 (Jurkat)
23 nM
IC50 (THP1)
47 nM
IC50 (IL8)
N/A
IC50 (TNFα)
N/A
staurosporine
dexamethasone
N/A
N/A
80 nM
34 nM
Experimental values show that the majority of the
investigated compounds are lipophilic (Table 2), which can
be favorable in CNS terapeutic area. Correlation between
calculated logP and experimental Chrom logD values
qualitative agreement was observed between calculated
logP and experimental Chrom logD especially for fused
hetero-benzoxazoles 9 and 11 (Table 2), compounds which
also inhibited TNFα protein expression in LPS stimulated
PBMC (Figure 8), indicating possible antiinflammatory role
interesting to further investigate. In case of bicyclo[3.2.1]-
core correlation between calculated logP and experimental
Chrom logD values did not show good precision in
predicting lipophilicity, since Chrom logD is expected to
account for the ionizability of investigated compounds.
High-throughput chromatographic determination of lipo-
philicity enables quick classification of novel compounds.
From the group of benzobicyclic compounds 23–32, there are
no examples with promising antiinflammatory or antipro-
liferative activity. These physico-chemical properties and results
for biological activity are the reason why these compo-unds are
also tested for cholinesterase inhibitory activity and antioxidant
characteristics, the benzobicyclo[3.2.1]-derivatives showed
better results as potential cholinesterase inhibitors and the
oxazole derivatives having better antioxidant properties.[43,44]
Even though calculated logD and logP values do not
show great precision in predicting lipophilicity for analised
compounds, it can be used for qualitative prioritization of
virtual libraries (Figure 12).
Table 2. Chrom logD values determined for some
investigated compounds from the following equation:
chrom logD = 0.0857 × CHI – 2. Chromatographic Hydro-
phobic Index (CHI) values have been determined from
gradient retention times (tR) at pH 7.4.
Compound
CHIaverage
78.70
81.34
84.22
88.05
89.49
64.55
73.18
74.14
45.36
45.60
89.01
79.42
>100
Chrom logD
4.74
4.97
5.22
5.55
5.67
3.53
4.27
4.35
1.89
1.91
5.63
4.81
>5
LogP
2.88
2.65
2.65
2.97
2.97
2.05
2.9
1
2
3
4
5
6
7
8
2.9
9
1.6
11
14
22
23
24
27
28
29
1.57
2.97
2.88
3.77
2.58
5.16
5.53
4.89
71.26
110.84
n/a
4.11
7.50
n/a
n/a
n/a
compounds have been studied in terms of lipophilicity
expressed as chrom logD values and calculated logP.
6
5
4
3
2
1
0
R² = 0,8188
0,00
2,00
4,00
6,00
8,00
ChromLogD
Figure 12. Dependence of Calc LogP on ChromLogD for naphthoxazoles and fused hetero-benzoxazoles 1–9, 11, 14 and 22.
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I. ŠAGUD et al.: Antiinflammatory and Antiproliferative Activity of Photoproducts
9
Most CNS drugs have logP values less than 5 so it is
easily absorbed in blood brain barrier where active
diffusion of drug is likely to have most lipophilic area like
lipid bilayer of membrane and if the value is less than 0 it
will move toward hydrophilic compartment like blood
serum. For fused hetero-benzoxazoles 9 and 11 it is
achieved best correlation between Chrom logD and logP,
but values are low for potential CNS drugs. Compound 29
possessing the benzobicyclo[3.2.1]-octadiene structure has
potential to cross BBB using active diffusion.
Supplementary Information. Supporting information con-
sists of figures showing all investigated effects of both
groups of compounds. Supporting information to the paper
is attached to the electronic version of the article at:
https://doi.org/10.5562/cca3530.
PDF files with attached documents are best viewed with Adobe Acrobat
Reader which is free and can be downloaded from Adobe's web site.
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the University of Zagreb short term scientific support for
2018 under the title Synthesis and functionalization of novel
(hetero)polycyclic photoproducts and Fidelta Ltd.
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