Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2021.128194

Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound's pharmacology and provide guidelines for further lead optimization.

Full text of DOI:10.1016/j.bmcl.2021.128194

Bioorg. Med. Chem. Lett. 46 (2021) 128194
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors
as potential human dihydroorotate dehydrogenase inhibitors
a
b
b
c
b
´
´
Milena M. Petrovic , Cornelia Roschger , Sidrah Chaudary , Andreas Zierer ,
a
a
a,*
´
´
ˇ
´
Milan Mladenovic , Violeta Markovic , Snezana Trifunovic , Milan D. Joksovic
a Faculty of Science, Department of Chemistry, University of Kragujevac, R. Domanovica 12, 34000 Kragujevac, Serbia
b University Clinic for Cardiac-, Vascular- and Thoracic Surgery, Medical Faculty, Johannes Kepler University Linz, Krankenhausstraße 7a, 4020 Linz, Austria
c Faculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 158, 11000 Belgrade, Serbia
A R T I C L E I N F O
A B S T R A C T
Keywords:
Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by
Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and
all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared
heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic
properties were considered on the basis of experimentally determined logD values at physiological pH. The most
promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibi-
tory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH,
determined by means of molecular docking, revealed the compound’s pharmacology and provide guidelines for
further lead optimization.
Dihydroorotate dehydrogenase
hDHODH inhibitors
Quinoline-4-carboxylic acids
Lipophilicity
Molecular docking
The oxidation of dihydroorotate to orotate and subsequent Flavin
mononucleotide regeneration are essential biological processes in the
pyrimidine biosynthesis pathway.1 The only mitochondrial membrane-
associated enzyme, dihydroorotate dehydrogenase (hDHODH), cata-
lyzes this redox reaction using ubiquinone in the role of terminal oxidant
from the mitochondrial electron transfer chain. As a result of this con-
version, the cells synthesize uridine monophosphate, a vital building
precursor for the formation of ribonucleosides and deoxyribonucleo-
sides.2 Having in mind the significance of pyrimidine nucleotide for
cellular metabolism, blocking the pyrimidine synthesis pathway by
inhibiting hDHODH, could be a promising way in the treatment of
cancer,3 malarial and anti-infective diseases,4–5 rheumatoid arthritis,
psoriasis, and various autoimmune diseases.6–7
hDHODH (PTC299, S312, S416) with promising antiviral activity were
synthesized and tested against SARS-CoV-2 coronavirus9–10 ](Fig. 1).
Moreover, the well-known FDA-approved hDHODH inhibitor, Lefluno-
mide, and its active metabolite Teriflunomide, used in the treatment of
rheumatoid arthritis and multiple sclerosis, have also shown antiviral
action against SARS-CoV-2.11 Another hDHODH inhibitor, Na-Brequinar
did not pass the phase II clinical trials for solid tumors because of its poor
solubility, increased concentration in blood, and formation of molecular
aggregates.3 One of the most potent hDHODH inhibitors containing
quinoline-4-carboxylic acid moiety is the antiviral C44 with diaryl ether
linkage and sufficient hydrophobicity required for excellent enzyme
inhibition.12 In addition, ether and ester derivatives of quinoline-4-
carboxylic acids exhibited good hDHODH inhibition activity and in
vitro antiproliferative action against colorectal adenocarcinoma HT-29
and breast MDA-MB-231 cancer cells.13
The articles published in the last two years pointed out hDHODH as a
new target in antiviral therapy against RNA viruses, such as SARS-CoV-
2.8 Virus-infected cells have high metabolic activity and are very
dependant on hDHODH for their supply of pyrimidine nucleotides. Thus,
the inhibition of pyrimidine biosynthesis is recognized to achieve an
antiviral effect by prevention of viral genome replication and inhibition
of virus RNA transcription blocking the formation of viral proteins. In
the light of these observations, several potent inhibitors targeting
In the previous paper, we tested a series of quinoline-4-carboxylic
acids derived from alkylated phenolic aldehydes for their hDHODH
inhibitory activity and cytotoxicity against normal HaCaT cell line.14
The introduction of hydrophobic groups at 3′ and 4′ position demon-
strated better hDHODH inhibition, increasing the cytotoxic activity of
these compounds towards healthy cells at the same time. Our intention
* Corresponding author.
´
E-mail address: mjoksovic@kg.ac.rs (M.D. Joksovic).
https://doi.org/10.1016/j.bmcl.2021.128194
Received 14 May 2021; Received in revised form 3 June 2021; Accepted 6 June 2021
Available online 8 June 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

´
M.M. Petrovic et al.
Bioorganic & Medicinal Chemistry Letters 46 (2021) 128194
to achieve low cytotoxic potential retaining good hDHODH inhibitory
activity led us to the synthesis of novel quinoline-4-carboxylates derived
from vanillin, modified with more polar substituents at 4′ position of the
aromatic ring.
against HaCaT cell line (Table 2). The optimal pharmacological profile
may be attributed to 5j with good enzyme inhibition (IC50 = 0.5
μM) and
low cytotoxic activity towards HaCaT cells (IC50 > 300
μM). The phenyl
ring with electron-donating methyl groups (5b, 5c, 5d) as well as n-
hexyl, cyclohexyl, and adamantyl groups directly attached to amide
nitrogen demonstrated poor enzyme inhibition despite low anti-
proliferative potential against HaCaT cell. Finally, heteroaromatic sub-
stitution, except 5o, demonstrating excellent cytotoxic properties, was
less fruitful as indicated by the weak hDHODH inhibition exhibited by
furane and thiophene analogs (5p, 5q).
Pfitzinger and Doebner reactions are two usual ways for the prepa-
ration of quinoline-4-carboxylic acids. In Pfitzinger condensation, isatin
and carbonyl compound react in the presence of strong base,15 while
Doebner method is a three-component reaction of anilines, benzalde-
hydes and pyruvic acid.16 Unfortunately, both synthetic pathways suffer
from long reaction time and low yields, especially when more
substituted ketones and aldehydes were used. Thus, readily available
and cheap vanillin’s precursors were applied in multicomponent
Doebner reaction for the synthesis of our targeted quinoline-4-
carboxylic acid derivatives.
Together with low cytotoxicity, lipophilicity plays a crucial role in
the drug discovery process due to its association with the absorption,
distribution, metabolism, excretion, and toxicity (ADMET) of drug
candidates.19 The moderate lipophilic properties of compounds (logD7.4
= 0–3), retaining good potency at the same time, show an excellent
balance between permeability and solubility. Highly lipophilic com-
pounds (logD7.4 > 3.5) have poor aqueous solubility and greater possi-
bility to inhibit Cytochrome P450 enzymes, while negative values of
logD7.4 lead to low permeability throw biological membranes.20 All our
quinoline-4-carboxylic acids are at least partly charged at physiological
pH (7.4) due to the presence of ionizable COOH group and logD is the
accurate parameter of compound lipophilicity. Except for 5o, 5p, and
5q, all other compounds are in the optimal range of logD7.4 values
(Table 2). Several compounds 5c, 5f, 5h and 5j displayed excellent
lipophilic properties where 5j show practically ideal lipophilicity and
The synthetic route for the desired quinoline-4-carboxylic acid de-
rivatives is presented in Scheme 1. Firstly, vanillin was alkylated with
monochloroacetic acid according to a known procedure.17 The alkylated
compound 2 was converted into acid chloride 3 in the reaction with
thionyl chloride in the presence of catalytic amount of DMF. The in-
termediate 3 was transformed to amide without its isolation by the re-
action with primary amines, using solid NaHCO3 for neutralization of
liberated HCl.18 The final quinoline-4-carboxylates were obtained in
Doebner multicomponent reaction of various O-alkylated aldehydes
containing amide moiety, pyruvic acid and aniline. All synthesized
compounds were structurally characterized using elemental analysis, as
well as IR and NMR spectroscopy (Supplementary content).
the best pharmacological profile including its low cytotoxicity (IC50
300 M) and good hDHODH inhibitory activity (IC50 = 0.5 M), as
stated above.
>
In order to get an insight into SAR studies, different electron-
donating and electron-withdrawing groups at the terminal phenyl ring
are introduced for enzyme inhibition assay and cytotoxic activity against
normal HaCaT cell. The enzyme inhibitory activity strongly depends on
the kind and position of substituents (Table 1). Generally, appropriate
halogen substitutions (F, Cl, CF3) gave good hDHODH inhibitory activ-
ity, especially when fluorine is present at position 2 (5e), chlorine at
position 3 and 4 (5i, 5j), and CF3 group at position 2 and 3 (5k, 5l). The
5k is the most potent compound, but with the highest cytotoxicity
μ
μ
The SAR analysis was validated on the structure-based level,
following the guidelines reported in our previous study,14 by means of
determining the bioactive conformations of targeted compounds,
through which the hDHODH inhibition was exerted. The hDHODH is
compiled of two domains21: a larger C-terminal domain, as a redox site
for dihydroorotate (substrate) and flavine mononucleotide (FMN,
cofactor), and a smaller N-terminal domain, connecting hDHODH with
Fig. 1. Chemical structures of some hDHODH inhibitors.
2

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M.M. Petrovic et al.
Bioorganic & Medicinal Chemistry Letters 46 (2021) 128194
Scheme 1. Reagents and conditions: a) ClCH2COOH, NaOH, H2O, 100 min., reflux, HCl; b) SOCl2, DMF, CH2Cl2, 12 h, r.t.; c) Ar(R)NH2, NaHCO3, CH2Cl2, 4.5 h, r.t.;
d) EtOH, 3 h, reflux.
Table 1
Table 2
Inhibition of human dihydroorotate dehydrogenase (hDHODH) by quinoline-4-
carboxylic acid derivatives 5a-t.
IC50 values (μM) found for the normal HaCaT cell lines after treatment with the
quinoline-4-carboxylic acids 5a-t and their logD7.4 values obtained experimen-
tally by shake-flask method in two-phase n-octanol/phosphate buffer system.
Compd.
Compd.
IC50 ± SD (
μM)
Compd.
IC50 ± SD (μM)
IC50 ± SD (
μ
M)
logD7.4
5a
5b
5c
5d
5e
5f
3.9 ± 0.1
5.9 ± 0.9
1.9 ± 0.7
3.8 ± 0.7
0.5 ± 0.4
2.1 ± 0.4
1.6 ± 0.5
1.3 ± 0.1
0.5 ± 0.3
0.5 ± 0.1
0.3 ± 0.1
5l
0.5 ± 0.1
2.4 ± 0.2
3.7 ± 0.5
0.7 ± 0.3
1.0 ± 0.1
3.1 ± 0.9
2.7 ± 0.6
1.7 ± 0.3
1.7 ± 0.5
0.8 ± 0.1
5m
5n
5o
5p
5q
5r
5a
5b
5c
5d
5e
5f
˃300
0.7
0.8
1.5
1.2
0.9
1.6
1.1
1.6
2.3
1.5
1.3
1.3
1.6
0.4
ꢀ 0.8
ꢀ 0.3
0.0
1.0
0.8
1.0
230 ± 4
225 ± 6
˃300
161 ± 5
148 ± 5
286 ± 11
210 ± 8
192 ± 4
˃300
5 g
5 h
5i
5 s
5 t
Sa
5g
5h
5i
5j
5 k
5j
5k
5l
102 ± 6
160 ± 3
150 ± 5
˃300
a
Leflunomide, a FDA approved reference hDHODH inhibitor.
5m
5n
5o
5p
5q
5r
5s
5t
˃300
the internal mitochondrial membrane, with a narrow tunnel through
which the ubiquinone (the second cofactor) easily approaches the FMN
for the redox reaction (for detailed topography analysis reader is
referred to our previous publication.14 Hence, the targeted compounds
occupied the hDHODH’s narrow tunnel, adopting highly conserved
binding modes (Fig. 2, Supplementary content Figs. S1-S19), compara-
ble to either clinical drug leflunomide (PDB ID 3F1Q)21 or co-
˃300
˃300
˃300
˃300
180 ± 7
carboxylic acid formed strong hydrogen bonds via the carbonyl moiety
crystallized 4-quinoline carboxylic acids, brequinar (PDB ID 1D3G)22
,
with Arg136′s guanidino
ω-nitrogens (ω-N) (dHB lengths ranging from
2-(4-(2-Chloro-6-methylpyridin-3-yl)phenyl)-6-fluoro-3-methyl-
2.648 Å to 2.648 Å). On the other hand, the C-4 carboxylic acid’s hy-
droxyl group electrostatically interfered with the Gln47′s amide nitro-
gen. Latter interactions influenced the rectangular alignments of
quinoline-4-carboxylic acid (the product 43 in23 and 2-([1,1′-Biphenyl]-
4-yl)-3-methyl-1,7-naphthyridine-4-carboxylic acid (the product 46 in23
(PDB IDs 6CJF and 6CJG, respectively). Thus, the common C-4
3

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M.M. Petrovic et al.
Bioorganic & Medicinal Chemistry Letters 46 (2021) 128194
Fig. 2. The bioactive conformation of 5j as hDHODH inhibitor. For the clarity of presentation, the hydrogens were omitted, the N-terminal amino acids, orotate as
hDHODH substrate, and FMN as hDHODH coenzyme were depicted, whereas the remaining of the enzyme is illustrated with the surface. The established hydrogen
bonds are presented with black lines.
quinoline rings related to FMN, likely making a spatial barrier for the
ubiquinone approach. Within, the heterocycle’s phenyl moiety assured
distinct positioning with the aid of the T-shaped (i.e. edge to face) hy-
drophobic interactions with Val134, Val143, and Tyr356, T-shaped
induced-dipole interactions with Tyr147, eclipsed (i.e. face to face)
steric hindrance with Thr360′ side chain methyl group, and parallel-
displaced hydrophobic interactions with His56. The quinoline’s nitro-
gen was keen of the electrostatic interactions with Tyr356′phenolic
portion and likewise faced the Thr98′s side chain methyl group, as well
as the hPhe98 and hLeu359 hydrophobic portions in an induced-dipole
manner.
decrease. Hence, the 2-(trifluoromethyl)aniline moiety of the most
potent derivative, 5k (Supplementary content Fig. S1), occupied the
entrance of the narrow tunnel, where the aromatic portion exerted the
tendency for the eclipsed hydrophobic interactions with Phe62, and T-
shaped interactions with Tyr38 and Leu42. The o-trifluoromethyl res-
idue turned the hydrophobic portions of Met43, Leu46, and Leu58 into
dipoles. However, the m-CF3 incorporation (5l, Supplementary content
Fig. S3.) resulted in a decrease in potency, owed to the dipole induction
only within Leu58. Not even the m-CF3 to the p-CF3 substitution (5m,
Supplementary content Fig. S13) was beneficial for the potency,
revealing the benchmark for Leu42 in terms of toleration for electron-
withdrawing groups. With a decrease of electron-withdrawing poten-
tial toward the Leu42, upon the p-chloroaniline introduction, as in 5j
(Fig. 2), the slight potency drop occurred related to 5k: the p-Cl atom has
been positioned at the outskirts of the narrow tunnel, likely forming
induced dipole interactions with Leu42 of lower intensities. The p-Cl to
m-Cl substitution (5i, Supplementary content Fig. S2) resulted in a
further potency decrease, despite comparable interactions with Leu42,
highlighting the residue as tolerable to electron-withdrawing functional
groups. On the other hand, the o-Cl portion of 5h (Supplementary
content Fig. S7), seemed too weak to induce the dipole only within the
Leu58 (compare with 5k, Supplementary content Fig. S1), resulting in a
potency decrease. The Leu58 likewise interfered with the o-F portion
(5e, Supplementary content Fig. S4), still resulting in notable potency.
Paradoxically, either o-F to m-F (5f, Supplementary content Fig. S12) or
o-F to p-F moieties dispositioning was detrimental for the potency,
alienating the distinct portions from Leu42. The reduction in electron-
withdrawing potential, on the other hand, led to a more notable po-
tency decrease. Thus, while the 5o’s pyridine ring (Supplementary
content Fig. S5) still somehow drawn Leu42 (on the cost of parallel
displaced hydrophobic interactions with Phe62 and T-shaped in-
teractions with Leu58), 5p’s furan ring (Supplementary content Fig. S6.)
made no electron-withdrawing impact on either Leu42 or Leu58, as the
heterocycle’s oxygen atom was oriented toward the middle of the nar-
row tunnel (the furan ring to thiophene replacement, as in 5q (Supple-
mentary content Fig. S15), provoked even worst biological response
despite the sulfur atom’s interactions with Leu42). The incorporation of
electron-donating groups like cyclohexyl (5s, Supplementary content
Fig. S1), adamantyl (5t, Supplementary content Fig. S10), m-Me-ben-
zene (5c, Supplementary content Fig. S11), n-hexyl (5r, Supplementary
The incorporation of the 4-(carboxymethoxy)-3-methoxyphenyl
scaffold, introduced at the position C2 of quinoline-4-carboxylic acid,
resulted in the alterations of compounds’ binding modes. Thus, for all
the compounds but 5e (Supplementary content Fig. S4), 5 t (Supple-
mentary content Fig. S10), and 5r (Supplementary content Fig. S14), the
o-methoxy portion fitted snugly into the hydrophobic sub-pocket
compiled of Tyr38, Leu42, Met43, Leu42, Leu46, and Leu58. Conse-
quently, the o-methoxy group bearing’ aromatic portion established the
eclipsed hydrophobic interactions with Leu359 and the parallel-
displaced hydrophobic interactions with Phe98. Nevertheless, with the
change of o-methoxy group’s orientation toward the Phe98, Met111,
and Leu359 within the bioactive conformations of 5e, 5r, and 5t, (i.e.
upon the horizontal flip), the bearing aromatic moiety suffered trans-
versal translation toward the later hydrophobic pocket, forming dis-
placed T-shaped interactions with Tyr38, Met43, and Leu48, as well as
parallel displaced interactions with Phe62. However, 5e retained
notable potency, leading to the conclusion that other functional groups
were decisive in pharmacodynamics differences (see further discussion).
Anyhow, the alignment of the o-methoxyphenyl portion influenced the
spatial arrangement of the C4′-substituting 2-hydroxyacetic acid bridge,
which etheric oxygen atom faced the Met111′s -SH-CH3 for weak elec-
trostatic interactions while the carbonyl group electrostatically inter-
ference with Tyr38 side-chain phenolic moiety (the in-between
positioned methylene group gave the contribution by means of hydro-
phobic interactions with Leu68).
However, the more distinguished conformational differences among
the targeted compounds, associated with the potency differences, came
with the incorporation of various arylalkylamines, i.e. the formation of
amides. Therefore, further discussion will be correlated with the potency
4

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M.M. Petrovic et al.
Bioorganic & Medicinal Chemistry Letters 46 (2021) 128194
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In summary, a series of amide derivatives of vanillin were condensed
with aniline and pyruvic acid in a multicomponent Doebner reaction.
The chemical structures of all compounds were confirmed by NMR, IR,
and elemental analysis. In vitro hDHODH inhibition and antiproliferative
assays against normal HaCaT cell together with lipophilic properties
were used to evaluate the biological potential of the synthesized com-
pounds. The compound 5j demonstrated the most favorable pharma-
cological profile displaying good hDHODH inhibitory activity, low
cytotoxicity towards normal HaCaT cell, and excellent lipophilic prop-
erties. Molecular docking-determined bioactive conformations revealed
the pharmacology of targeted compounds on the hDHODH level and
provided guidelines for further lead optimization.
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Declaration of Competing Interest
13 Vyas VK, Qureshi G, Oza D, et al. Synthesis of 2-,4,-6-, and/or 7-substituted quinoline
derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and
anticancer agents: 3D QSAR-assisted design. Bioorg Med Chem Lett. 2019;29(7):
917–922. https://doi.org/10.1016/j.bmcl.2019.01.038.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
´
14 Petrovic MM, Roschger C, Chaudary S, et al. Potent human dihydroorotate
dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from
phenolic aldehydes: Synthesis, cytotoxicity, lipophilicity and molecular docking
studies. Bioorg Chem. 2020;105:104373. https://doi.org/10.1016/j.
bioorg.2020.104373.
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5