Quinolines derivatives as novel sunscreening agents

Article abstract of DOI:10.1016/j.bmcl.2013.06.046

Currently, the research and development of sunscreens play an important role on the synthesis of actives that are stable in various kinds of formulations - in addition to their efficiency and broad spectrum of protection against ultraviolet radiation. Our

Full text of DOI:10.1016/j.bmcl.2013.06.046

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4506–4510
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Quinolines derivatives as novel sunscreening agents
Hudson C. Polonini a, Rafael M. P. Dias b, Isabela O. Souza b, Karla Mara Gonçalves a, Tiago B. B. Gomes a,
Nádia R. B. Raposo a, Adilson David da Silva b,
⇑
a Núcleo de Pesquisa e Inovação em Ciências da saúde (NUPICS), Universidade Federal de Juiz de Fora, Campus Universitário, Juiz de Fora 36036-900, Brazil
b Departamento de Química, Universidade Federal de Juiz de Fora, Campus Universitário, Juiz de Fora 36036-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Currently, the research and development of sunscreens play an important role on the synthesis of actives
that are stable in various kinds of formulations—in addition to their efficiency and broad spectrum of pro-
tection against ultraviolet radiation. Our objective here was to synthesize new sunscreening chemical
agents using quinoline as a base molecule. Twelve quinoline derivatives were synthesized, four of them
novel molecules, and their photoprotective activity was determined in vitro using diffuse transmittance
spectrophotometry. We determined their SPF, UVAPF, UVA/UVB ratio, critical wavelength and Boots Star
Rating. The quinolines derivatives presented a varied profile of photoprotection, their SPF ranging from 2
to 11 and their UVAPF from 2 to 7. In terms of the critical wavelength, all molecules were considered of
broad-spectrum by different classifications. Regarding the Boots Star Rating, one compound received no
rating, seven of them received a three stars rating, three received a four stars rating and three were given
a five stars rating. The molecules showed in the present work have a wide range of possibilities for cre-
ating new sunscreen products, once they have good SPF or UVAPF for single molecules, and they also pos-
sess other different qualities that can act synergistically.
Received 9 April 2013
Revised 12 June 2013
Accepted 17 June 2013
Available online 26 June 2013
Keywords:
Photoprotective activity
Sunscreening agents/UV filters
Chemical synthesis
Ultraviolet radiation
Quinolines
Structure–activity relationship
Ó 2013 Elsevier Ltd. All rights reserved.
Despite the fact that ultraviolet (UV) radiation has beneficial ef-
fects on human health, such as the stimulation of the production of
vitamin D3, and involvement in bone metabolism and in the func-
tioning of the immune system,1 it is known that it also plays an
important role in the development of skin malignancies.2,3
These deleterious effects caused by the solar radiation occur be-
cause many molecules in the skin can absorb UV radiation and un-
dergo chemical changes due to such absorption. Among these, one
of the most-absorbing molecules is the DNA, whose UV absorption
may result in mutation, which subsequently may lead to malignant
transformation of the cell, that is, skin cancers.4
Skin cancer has a high incidence worldwide: it is estimated that
among every three new cases of cancer, one will be diagnosed as
skin cancer — and the prediction is that this number shall increase
even more. This represents a serious public health issue, consider-
ing the future implications that may result from decades of con-
stant exposure to sunlight.5
cases of non-melanoma skin cancer are preventable through the
correct use of these products.5,7
Nevertheless, sunscreens are considered cosmetic products in
most countries, and the segment of photoprotection has set the
bar high in terms of quality requirements and innovation potential
for the entrance of new products. Currently, the research and
development of sunscreens play an important role on the synthesis
of actives that are stable in various kinds of formulations, in addi-
tion to being efficient and presenting broad spectrum of protection
against ultraviolet radiation.8
In this context, our work aimed to synthesize new sunscreening
chemical agents using the quinoline as a base molecule, and also to
determine their photoprotective activity in terms of Sun Protection
Factor (SPF), Protection against UVA-rays (UVAPF), UVA/UVB ratio,
critical wavelength and Boots Star Rating.
The 4-aminoquinoline derivatives were synthesized by a gen-
eral procedure showed in Scheme 1. The common starting mate-
rial, 4,7-dichloroquinoline (2.5 mmol), was solubilized in ethanol
(6.0 mL) at 50 °C, the correspondent amine (2.7 mmol) was added
and then the mixture was heated under gentle reflux for 8 h and a
precipitate was formed. The system was cooled and filtered, fol-
lowed by washing with cold ethanol. All the compounds were
characterized by one-dimension nuclear magnetic resonance (1D
NMR), infrared (IR) spectroscopy and melting point (MP) and were
in accordance with data in the literature. Nicotinic hydrazide used
for the synthesis of compound K and 7-chloro-4-hidrazynilquino-
line used for the synthesis of compound J were obtained following
In this light, the use of sunscreens is well-known to be an effec-
tive and low-cost measure in preventing the development of skin
cancers triggered by UV radiation.6 It is estimated that minimally
10% of all new cases of such malignance could be avoided if people
took the proper and continuous use of sunscreens, and that 78% of
⇑
Corresponding author. Tel.: +55 21023310; fax: +55 21023314.
E-mail address: david.silva@ufjf.edu.br (A.D. da Silva).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.06.046

H. C. Polonini et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4506–4510
4507
R3
A: R1 = OH ; R2 = R3 = H
B: R1 = COOH; R2 = R3 = H
C: R1 = H; R2 = OH; R3 = COOH
D: R1 = R2 = R3 = H
HN
N
R2
R1
Cl
a
H
O
S
N
Cl
N
R'
O
H
E:
a
HN
Cl
N
S
R' =
F:
H:
I:
4,7-dichloroquinoline
N
N
Cl
N
N
G:
a
O
N
H
N
J:
H
HN
R ''
O
K:
R '' =
N
Cl
N
L:
a: amine, EtOH, reflux,
Scheme 1. Synthetic pathway for quinoline derivatives.
methods from the literature.9,10 Spectral data of the non-novel
compounds are available in the references from Table 1, and the
data from the novel compounds are available as Supplementary
data.
prevent the immunosuppression and skin tumor induction by UVB
irradiation. This has a great relevance, because one can infer that
the compound K not only has an immediate benefit for skin, once
it protects directly the skin from the sun rays, but also a long-term
benefit, by preventing the sun-mediated immunosuppression.
Apart from these two main compounds, a series of 4-amino-
quinolines derivatives were synthesized by the reaction of
4,7-dichloroquinoline with the corresponding sulfas, phenyl,
hydroxyphenyl and carboxyphenyl derivatives, and they also
presented a significant photoprotection for a single UV-filter sub-
stance. Although they possess a minor UVA protection compared
to J and K, they can contribute to the photoprotection effect when
used synergistically in a sunscreen formulation. This is of sheer
relevance, as UVA rays are known to play an important role on skin
cancers.
In fact, one the major reasons why new sunscreens are still
being developed is the relatively recent perception of the deleteri-
ous effect of the UVA radiation on different photodermatoses, on
the development of skin cancers, on photo-immunosuppression
and on photoaging. The advances in the comprehension of these
processes have been leading to the development of new ultraviolet
filters with increased capacity of broad-spectrum protection (i.e.,
against UVA and UVB radiations).24
This being taken into account, new measures of broad-spectrum
protection were created. One of these is the Critical Wavelength,
defined as the wavelength at which the integral of the area under
the absorption spectrum of the sample reaches 90% of the total
absorption, from 290 to 400 nm.25 The classification of the spec-
trum, however, can be different according to the reference
adopted. For instance, the US Food and Drug Administration
(FDA)26 classifies products on a scale consisting of five numerical
categories: 0 (kc <325 nm), 1 (325 6 kc < 335), 2 (335 6 kc < 350),
3 (350 6 kc < 370) and 4 (370 6 kc). Under such classification, all
derivatives are Category 4, the highest one, and so they can be
considered as broad-spectrum sunscreens. Another possible classi-
fication is the one created by Springsteen et al.,27 who classifies
broad-spectrum sunscreen products as those which have a kc value
The SPF — the measure of the UV solar energy required to pro-
duce sunburn on a skin area protected with a sunscreen product,
relative to the amount of solar energy (UVB) required to produce
the same sunburn on an unprotected skin area — is currently the
gold standard procedure to quantitate the solar protection pro-
vided by the products. However, in vitro photoprotection studies
are gaining relevance for determining the effective performance
of potential contenders for active sunscreen ingredients or final
products against UV radiation, before the more expensive in vivo
tests.19 In the present work, we used the diffuse transmittance
technique to determine the photoprotection profile of 12 quinoline
derivatives (among these, four are novel compounds).
Since the creation of the first chemical sunscreen in history, a
lotion containing acidified quinine sulfate,20 several sunscreens
were developed and commercially launched, but there are still
market opportunities for novel products with different properties
and actions. In this sense, we chose quinoline as a base molecule
due to its chemical similarity to quinine and also to quinone, an-
other molecule with well-known photoprotective activity.21
In fact, one can see in Table 1 that the quinolines derivatives
presented a varied profile of photoprotection, the SPF ranging from
2 to 11 and the UVAPF from 2 to 7. The compound J, which has in
its structure a hydrazine group connected to a 7-chloroquinolone,
was the one who presented greater SPF and UVAPF, followed by the
compound K. We must also highlight that the compound J was
capable of absorbing UVA rays more effectively than other
compounds.
Interestingly, the second most active compound (K) was the one
with an addition of the group nicotinamide (or niacinamide),
which is known to prevent immunosuppression caused by UVA
and UVB radiation.22 Yet, a study conducted by Gensler23 showed
that the application of nicotinamide to UV-irradiated mice reduced
skin tumor incidence from 75% to 42.5%, which points that it could

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H. C. Polonini et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4506–4510
Table 1
Photoprotection results of quinolone derivatives
c
Substance
SPFa
UVAPFb
kc (nm)
UVA/UVB ratio
0.871
HN
A11
4
0.9
0.5
0.1
0.0
3
4
3
3
0.8
0.4
0.1
0.1
387
389
388
385
OH
Cl
Cl
N
HN
B12
C13
D14
3
3
4
1.186
1.030
0.786
COOH
N
COOH
HN
OH
Cl
Cl
N
HN
N
O
S
NH2
O
HN
E (novel)
F (novel)
G (novel)
3
2
2
0.2
0.3
0.1
3
2
2
0.4
0.5
0.3
388
388
386
1.161
0.888
0.849
Cl
N
H
O
S
N
O
N
HN
N
Cl
H
O
S
N
N
O
N
HN
Cl
Cl
N
H
O
N
O
S
S
N
H15
HN
N
4
0.4
2
0.3
385
0.742
H
O
N
O
S
N
O
I16
4
0.0
2
0.2
381
0.598
HN
N
Cl

H. C. Polonini et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4506–4510
4509
Table 1 (continued)
c
Substance
SPFa
UVAPFb
kc (nm)
UVA/UVB ratio
NH2
HN
N
J17
11 0.1
7
0.2
376
377
0.612
Cl
N
H
N
HN
K (novel)
6
3
0.3
0.4
4
0.6
0.710
O
Cl
Cl
N
H
N
HN
L18
3
0.8
384
0.844
N
a
Sun Protection Factor.
UVA Protection Factor.
Critical wavelength Value.
b
c
Table 2
Boots Star Rating criteria for classification of UVA protection in sunscreens
Initial Mean UVA/UVB ratio
0.0 to 0.59
0.6 to 0.79
0.8 to 0.89
0.89 and over
Post exposure mean UVA/UVB ratio
0.0 to 0.56
No rating
No rating
No rating
No rating
No rating
⁄ ⁄ ⁄
No rating
⁄ ⁄ ⁄
No rating
⁄ ⁄ ⁄
0.57 to 0.75
0.76 to 0.85
0.86 and over
⁄ ⁄ ⁄
⁄ ⁄ ⁄ ⁄
⁄ ⁄ ⁄ ⁄
⁄ ⁄ ⁄ ⁄
⁄ ⁄ ⁄ ⁄ ⁄
⁄ ⁄ ⁄
greater than 370 nm. Thus, the previously mentioned analogues
may also be considered broad-spectrum products by this classifica-
tion, offering protection against both UVA and UVB.
Acknowledgments
We thank CNPq, CAPES, FAPEMIG and PROPESQ/UFJF.
Another measure of the spectrum of protection that we have
performed was the determination of the UVA/UVB ratio, which
provides a good idea of which UV region is better blocked by each
substance. The UVA/UVB ratio can also be used to provide the so-
called Boots Star Rating,28 which classifies the products in catego-
ries from 0 to 5 stars. Such classification should be done according
to Table 2.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.06.
046.
The Boots Star Rating is important to determine not only the
spectrum of protection, but also the stability of the generated
photoprotection values, since the components of the sunscreens
may degrade. Following this classification method, one compound
received no rating (I), seven of them received a three stars rating
(D, G, H, J and K), three received a four stars rating (A, F and L)
and three were given a five stars rating (B, C and E).
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