Synthesis and antifungal activity of new hybrids thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazole

Article abstract of DOI:10.1016/j.bmcl.2021.127944

Synthesis and antifungal activity of hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazoles are presented. The solubility and lipophilicity of compounds was assessed and it was discovered that compounds with piperazine linker exhibited significant

Full text of DOI:10.1016/j.bmcl.2021.127944

Bioorg. Med. Chem. Lett. 40 (2021) 127944
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antifungal activity of new hybrids thiazolo[4,5-d]pyrimidines
with (1H-1,2,4)triazole
,
Svetlana V. Blokhinaa, Angelica V. Sharapovaa *, Marina V. Ol’khovicha, Irina A. Doroshenkob,
Igor B. Levshinc, German L. Perlovicha
a G. A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya Street, 153045 Ivanovo, Russian Federation
b M. V. Lomonosov Moscow State University, Department of Chemistry, 27/1 Lomonosovsky Avenue, 117901 Moscow, Russian Federation
c Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, 119021 Moscow, Russian Federation
A R T I C L E I N F O
A B S T R A C T
Keywords:
Synthesis and antifungal activity of hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazoles are presented.
The solubility and lipophilicity of compounds was assessed and it was discovered that compounds with piper-
azine linker exhibited significant antifungal activity against filamentous and yeast fungi.
Hybrids
Thiazolo-pyrimidins
Triazole
Lipophilicity
Solubility
Antifungal activity
The last few decades have seen a considerable increase in fungal
diseases and emergence of resistance to the most popular antifungal
drugs belonging to many chemical classes, which makes treatment of
patients more difficult. Fungal infections are especially dangerous in
patients with a weakened immune system destroyed by cancer, HIV,
immunosuppressive drugs or other diseases.1,2 The enormous amount of
available data on the chemical characteristics and biological activity of
(1H-1,2,4)triazole derivatives allows researchers to consider these sub-
stances to be one of the most promising classes of drug compounds.3,4
Several compounds bearing (1H-1,2,4)triazole core, display diverse
bioactivities exhibit antibacterial, analeptic, anti-inflammatory, car-
dioprotective and other types of activity.5 Common antifungal drugs –
fluconazole, itraconazole, isavuconazole, efinaconazole, etc. – have a
triazole fragment in the structure of their molecules. The mechanism of
azole action is associated with inhibiting P450 cytochrome enzymes
catalyzing lanosterol transformation into ergosterol, which leads to the
destruction of the fungus cell membrane.6
example would be the tetrahydro-thiazolo-pyridine hybrids with high
antifungal activity and water solubility.11,12 The effectiveness of the
action of the hybrids with various thienopyrimidones was demonstrated
on experimental models of systemic candida infections.13 The high ac-
tivity indicator was also achieved in the tests of various condensed
pyrimidones with benzothiazoles.14 In the present work, thiazolo[4,5-d]
pyrimidine was used as a component of the hybrid molecule. The de-
rivatives with this fragment potentially have biological relevance as
analgesics, central nervous system depressants, and bronchodilators and
are also recommended for prevention and treatment of atherosclerosis,
diabetes and other diseases.15,16
Another important fragment incorporated into the molecular struc-
ture of the synthesized compounds is piperazine.17,18 In combination
with various heterocyclic fragments piperazine significantly improves
the biological properties of the compounds, including their antimicro-
bial activity.4,19 Obtained hybrid compounds consist of three compo-
nents specified earlier: (1H-1,2,4)triazole, thiazolo-pyrimidine, and
piperazine. We have also studied the effect of the structure of the linker
between the heterocycles and substituents of various chemical nature on
the in vitro antifungal activity of the synthesized substances. Besides,
since lipophilicity is the key parameter responsible for the biological
action of a drug,20 one of the aims of the work was to experimentally
determine the coefficient of distribution of the hybrid derivatives in the
1-octanol/buffer pH 7.4, as well as the equilibrium solubility of the
Hybridization approach combining triazole and different heterocycle
via a linker has been extensively used for discovery of new antifungal
agents.7–9 This principle has been used to obtain a lot of drugs of the
triazole group, including ravuconazole and its commercial water-soluble
analogue – isavuconazole – representing a triazole hybrid with thia-
zole.10 Sulfur-containing heterocycles are often used by researchers as
one of the components of the hybrid molecule based on triazole. An
* Corresponding author.
E-mail address: avs@isc-ras.ru (A.V. Sharapova).
https://doi.org/10.1016/j.bmcl.2021.127944
Received 13 November 2020; Received in revised form 1 March 2021; Accepted 2 March 2021
Available online 11 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

S.V. Blokhina et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127944
compounds in the aqueous and organic phases used. The aim of the
synthesis of the hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)
triazole and of the comprehensive study of their pharmaceutically
relevant physicochemical properties was to find the “structure–activity”
correlation in the series of the heterocyclic substances obtained.
Triazole oxirane was synthesized by the known method from 2,4-
difluoroacetophenone by treating it with trimethylsulfoxonium iodide
in toluene.21 The obtained amino derivative of triazole (2) is acylated
with acetyl chloride in dichloromethane to form the acetylamine de-
rivative of triazole (3) (Scheme 1).
yl]-2-hydroxy-propyl]-3-(R1,R2-phenyl)-2-thioxo-thiazolo[4,5-d]pyr-
imidin-7-one (IIIa-d), 6-[3-[4-[2-(2,4-difluorophenyl)-2-hydroxy-3-
(1H-1,2,4-triazol-1-yl)propyl]piperazin-1-yl]propyl]-3-(R1,R2-phenyl)-
2-thioxo-thiazolo[4,5-d]pyrimidin-7-one (IVa-c) and 6-[2-[4-[2-(2,4-
difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]piperazin-1-
yl]ethyl]-3-(R1,R2-phenyl)-2-thioxo-thiazolo[4,5-d]pyrimidin-7-one
(Va, b).
The detailed description of synthesis of 16 novel hybrids has been
presented in Supplementary material. The purity of synthesized com-
pounds has been determined by 1H NMR and 13C NMR measurements
and all results were 95–98%. The graphical 1H NMR and 13C NMR
spectra of compounds also have been provided in Supplementary ma-
terial. The obtained hybrids thiazolo[4,5-d]pyrimidines with 1,2,4-tria-
zole are amorphous, which was confirmed by PXRD method. As
example, the typical PXRD pattern (amorphous halo) for compound Ia
was shown in Fig. S1 (Supplementary material).
The sulfur-containing fragment in the thiazolo[4,5-d]pyrimidines
was prepared by the known method developed by Gewald22 and
described for one of the compounds with a fluorine substituent in the
para-position of the phenyl core in position 3 of the thiazole core that
was used.23 The synthesis of the hybrids of thiazolo[4,5-d]pyrimidines
with (1H-1,2,4)triazole (Groups I, II) was carried out according to
Scheme 2.
Sixteen novel hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)
triazole have been synthesized in this work. Their structural formulas
are shown in Fig. 1. It should be noted that in all compounds the methyl-
(a), fluoro- (b) and chloro- (c) substituents are introduced in the para
position of the phenyl ring, while the methoxy group (d) is the ortho
substituent.
As the first step, we studied and tested the scheme of synthesizing
thiazolo-pyrimidine hybrids with triazole through direct condensation
of the dihydrothiazolopyrimidine derivatives with triazole oxirane
prepared in advance. Among the possible variants of preparation of the
target products in different solvents – acetonitrile, ethanol, and toluene
with triethylamine and ammonium chloride additives – we selected
synthesis with triazole oxirane in dimethyl formamide for 2–3 days with
the formation of 6-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-tri-
azol-1-yl)propyl]-3-(R1,R2-phenyl)-2-thioxo-thiazolo[4,5-d]pyrimidin-
7-one that had not been described earlier. Three compounds with
different substituents in the phenyl ring were obtained: R1–CH3, R2–H
(Ia), R1–F, R2–H (Ib) and R1–H, R2–OCH3 (Id). Their molecular struc-
tures are shown in Scheme 2.
The bioactivity of the synthesized hybrids depends on their solubility
in pharmaceutically relevant media and lipophilicity to a large extent.
That is why we also experimentally measured the solubility of some
derivatives under study in the buffer pH 7.4 simulating the intestinal
fluid. Another important solvent used was 1-octanol, which simulates
amphipathic lipids of biological membranes. Besides, in order to study
the lipophilicity, we determined the distribution coefficients of the
compounds in the 1-octanol/buffer pH 7.4. The results are summarized
in Table 1. It is quite interesting to compare the data about the solubility
and distribution of the synthesized hybrid derivatives containing a flu-
conazole fragment in the molecular structure with the characteristics of
individual fluconazole that have been determined by us earlier25 and are
given in Table 1.
The reaction of the acetamide triazole chloro-derivative (prepared
from triazole oxirane in the process of consecutive interaction with
aqueous ammonia and then with chloroacetyl chloride in methylene
chloride) with thiazolo pyrimidines led to the formation of hybrid de-
rivatives with an amide linker (Group II). As a result, the target 6-[2-
(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-2-[3-
(R1,R2-phenyl)-7-oxo-2-thioxo-thiazolo[4,5-d]pyrimidin-6-yl]acet-
amides (IIa-d) were obtained.
The molar solubility of the substances in the buffer pH 7.4 (logSb)
changes by three orders of magnitude depending on the linker structure
and the substituent introduced into the thiazolo-pyrimidine fragment.
And in this case, all the compounds have much lower solubility in the pH
7.4 buffer than fluconazole.
The synthesis of the thiazolo[4,5-d]pyrimidines hybrids with (1H-
1,2,4)triazole (Groups III-V) was carried out according to Scheme 3.
A series of hybrid derivatives containing a certain linker between the
heterocycles – triazole and pyrimidino[4,5-d]thiazol – was obtained by
alkylation of the piperidine fragment imino group with haloalkyl (8).
For that purpose we used commercial haloalkyl Boc-piperazines: tert-
butyl 4-(2-bromoethyl)piperazin-1-carboxylate and tert-butyl 4-(3-bro-
mopropyl)piperazine-1-carboxylate, as well as the product of Boc-
piperazine condensation with racemic epichlorohydrin produced by
the method described in patent literature.24
An analysis of the effect of the chemical nature of the substituents in
the phenyl ring of the compounds with an acetamide linker on the sol-
ubility in the aqueous medium (logSb) has shown that the derivatives
can be arranged in the following order of increasing solubility: IIb(p-
fluoro-) < IIc(p-chloro-) < IIa(p-methyl-) < IId(o-methoxy-). It has been
established that all the synthesized substances with a methoxy-
substituent have better solubility than the methyl-derivatives. Accord-
ing to the literature data,26 the obtained result is explained by a stronger
destructive effect of the compounds with substituents in the ortho-po-
sition of the phenyl ring on the solvent structure than that of the para-
substituted derivatives.
After removing the Boc-protection from compound the obtained
products (9–11) by trifluoroacetic acid in methylene chloride, the
resulting piperazinyl thiazolo[4,5-d]pyrimidine derivatives (12–14)
were condensed by triazole oxirane in an alcohol with triethylamine and
ammonium chloride to obtain target derivatives: 6-[3-[4-[2-(2,4-
difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]piperazin-1-
The results of the study of the linker structure of the compounds’
solubility allowed us to make some conclusions about the interconnec-
tion between the molecular structure and solubility in the buffer pH 7.4.
H2
H
b. ClCOCH2Cl, NEt3, DCM
a. NH3 , H2O/EtOH = 2/5
0 oC, 12 h, 65 %
0 oC, 12 h, 80 %
OH
3
2
1
Scheme 1. Synthesis of triazole derivatives (2, 3).
2

S.V. Blokhina et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127944
R1
R2
Ia: R1 = CH3, R2 = H
OH
Ib: R1 = F, R2 = H
е. 1,
Id: R1 = H, R2 = OCH3
K2CO3 , NH4Cl,
DMF
120 oC,
Ia-c
36h, 24-42%
R1
R1
R1
c.
Sulfur, NEt3 EtOH,
reflux, 1 h, 63-78%
NC
CONH2
d. HC(OEt)3/
Ac2O =3/1
H2N
R2
R2
R2
reflux, 3 h, 66-74%
H2N
R1
NCS
K2CO3 ,
f. 3,
KI, DMF
7a-d
4
6a-d
100 oC,
5a-d
R2
7h, 55-80%
IIa: R1 = CH3, R2 = H
OH
IIb: R1 = F, R2 = H
IIc: R1 = Cl, R2 = H
IId: R1 = H, R2 = OCH3
IIa-d
Scheme 2. Synthesis of the hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazole (compounds of Groups I, II).
R1
R1
R2
g. K2CO3,KI
R2
Hal
Boc
Boc
X
DMF, 100 o
15 h, 42-49 %
C
X
h. CF3COOH, DCM,
20 oC, 8h, 90-94%
9-11a-d
7a-d
8
R1
R1
R2
NEt3 , EtOH, NH4Cl
R2
H
i.
X
reflux, 48 h,
25-44%
X
OH
12-14a-d
1
III-Va-d
Group III
H
Group IV
Group V
X =
X =
X =
IVa: R1 = CH3, R2 = H
IVb: R1 = F, R2 = H
Va: R1 = CH3, R2 = H
Vb: R1 = F, R2 = H
IIIa: R1 = CH3, R2 = H
IIIb: R1 = F, R2 = H
IIIc: R1 = Cl, R2 = H
IVc: R1 = Cl, R2 = H
IIId: R1 = H, R2 = OCH3
Scheme 3. Synthesis of the hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazole (compounds of Groups III-V).
3

S.V. Blokhina et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127944
R1
R1
R2
R2
H
OH
IIa: R1 = CH3, R2 = H
FCZ
Ia: R1 = CH3, R2 = H
Ib: R1 = F, R2 = H
Id: R1 = H, R2 = OCH3
IIb: R1 = F, R2 = H
IIc: R1 = Cl, R2 = H
IId: R1 = H, R2 = OCH3
OH
R1
OH
R1
R1
H
R2
R2
R2
OH
OH
IVa
:
R1 = CH3, R2 = H
IIIa: R1 = H, R2 = CH3
IIIb: R1 = F, R2 = H
OH
Va
Vb: R1 = F, R2 = H
:
R1 = CH3, R2 = H
IVb: R1 = F, R2 = H
IVc: R1 = Cl, R2 = H
IIIc: R1 = Cl, R2 = H
IIId: R1 = H, R2 = CH3
Fig. 1. Structural formulas of the synthesized compounds (Groups I-V).
lipophilicity limit determined empirically is expressed by the inequality:
ꢀ 0.5 < logPo/b < 5.28,29 The logPo/b values of the studied compounds
range from 0.44 to 4.10, which indicates their optimal lipophilicity for
pharmaceutics. The combination of several pharmacophore groups in
the hybrid molecules has led to a considerable increase in the molecular
weight of the substances up to over 500 g∙molꢀ 1, which is a violation of
Lipinski’s rule of five.29 It should be said that the molecular weight of
the commercial antifungal drugs is often higher than the limit set by this
rule. The number of hydrogen bond donors in the molecules of the de-
rivatives does not exceed three, which corresponds to the values rec-
ommended for drug compounds. However, the number of hydrogen
bond acceptors only for the compounds of the first group is less than ten,
whereas the number for the other substances is higher than the limit set
by the rule of five.
Table 1
Solubility and lipophilicity of synthesized compounds.
No
alogSb
blogSo
clogPo/b
1a
ꢀ 3.85
ꢀ 3.55
ꢀ 3.59
ꢀ 3.75
ꢀ 4.12
ꢀ 3.81
ꢀ 3.27
ꢀ 3.38
ꢀ 3.91
ꢀ 3.50
ꢀ 4.17
ꢀ 4.40
ꢀ 1.85
ꢀ 1.35
ꢀ 1.50
ꢀ 1.55
ꢀ 2.63
ꢀ 2.62
ꢀ 2.41
ꢀ 1.88
ꢀ 1.41
ꢀ 0.74
ꢀ 2.25
ꢀ 1.91
ꢀ 2.54
ꢀ 1.56
0.79
0.47
1.19
1.27
0.79
1.16
0.80
2.91
4.10
2.40
1.65
2.9
1b
1d
IIa
IIb
IIc
IId
IIId
IVa
IVb
IVc
Va
FCZ
0.44
The serial dilution micromethod was used to determine the anti-
fungal activity of the substances under consideration.30 The antifungal
activity was studied on the following cultures: C. parapsilosis ATCC
22019, C. albicans ATCC 24433, C. albicans 8R, C. albicans CBS8837, C.
albicans 604M, C. utilis 84, C. tropicalis 3019, C. glabrata 61 L, C. krusei
432M, Cryptococcus neoformans, A. niger 37a yeast fungi and filamentous
fungi: M. canis B-200 and T. rubrum 2002. Commercially available anti-
fungal agent such as Fluconazole (Quimica Sintetica S.A, Spain, purity
≥ 0.99%) were used as positive control drugs for comparison. By
combining triazole and thiazolo-pyrimidine fragments in a hybrid
molecule we managed to obtain compounds with a wide spectrum of
antifungal activity. The results of the biological tests showed that the
change in the bridge group structure and introduction of substituents of
various chemical nature into the phenyl ring had a great effect on the
antifungal activity of the substances. All the synthesized compounds
(except derivatives of II group) exhibited microbiological activity
against the strains of the C. parapsilosis ATCC 22019 pathogenic fungi
with the MIC values ranging from 0.06 to 8 µg/mL.
a
logSb – solubility in buffer pH 7.4 (mol/L).
logSo – solubility in 1-octanol (mol/L).
b
c
logPo/b – distribution coefficients in 1-octanol/ buffer pH 7.4 system.
The best solubility values among the methyl-substituted derivatives
were found in compounds I a with a methylene bridge group and IIa
with an acetamide fragment. The solubility is lower in compounds IVa
and Va also with methyl- substituents and it is reduced by piperazine
introduction. However, if the number of methylene units increases from
two in compound Va to three in compound IVa, the solubility becomes
higher. This may be the result of higher flexibility of the bridge group
caused by the increase in the number of alkyl chain units. A study of the
compounds with halogen atoms as substituents has shown that the sol-
ubility of chloro-derivative IVc with a linker consisting of piperazine
and methylene groups, is lower than in chloro-substituted compound IIc
with an acetamide linker. On the contrary, fluoro-derivative IVb dis-
solves better than compound with fluoro-group IIb.
The introduction of a piperazine group into the hybrid molecule led
to a considerable increase in the antifungal action, which was observed
in all the compounds containing this group. The most active substances
among those studied are methyl-(IVa), fluoro-(IVb), chloro- (IVc),
methyl-(Va) and fluoro-(Vb), derivatives. The results of the study of the
MIC values of these compounds are summarized in Table 2.
The molar solubility of the synthesized substances in 1-octanol
(logSo) is 1–2 orders of magnitude higher than in the buffer pH 7.4
and ranges from ꢀ 2.63 to ꢀ 0.74. The solubility of compound IVa in 1-
octanol is highest. The better solubility of the compounds in 1-octanol
than in the buffer is explained by the strong intermolecular interaction
between the solute and the solvent due to dipole–dipole forces and
hydrogen bonds.
Besides, we defined the antifungal activity as excellent (0.06–2 µg/
mL), good (4–8 µg/mL), moderate (16–32 µg/mL), or poor (≥32 µg/mL)
based on the MIC values. As can be seen, the derivatives shown have a
piperazine group in the linker structure and differ from each other in the
The logPo/b values of the synthesized derivatives are below 3 (with
the only exception being compound IVa). For comparison, the logPo/b
value of fluconazole is equal to 0.44.27 It should be noted that the drug
4

S.V. Blokhina et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127944
Table 2
The MIC results of the synthesized compounds.*
number of carbon atoms in the alkyl chain connecting this group with
the thiazolo-pyrimidine fragment. An analysis of the biotests has shown
that the antifungal activity is affected by both the structure of the bridge
group and the introduction of substituents into the aromatic ring
(Fig. 2).
1
2
3
4
5
6
7
8
9
35
30
25
20
15
10
5
For compounds with methylene linker (Group I), we observed only a
weak antifungal activity against the C. parapsilosis strain, and for com-
pounds with substituents – fluorine in the para position (Ib) and
methoxy – (Id) in the ortho position of the phenyl ring (MIC 8–16 μg /
ml). The introduction of an acetamide linker (Group II), regardless of the
substituents in the phenyl ring, completely deprived the molecule of
microbiological activity, and only with the addition of a cyclic amine –
piperazine (compounds of Groups III–V), we observed the appearance of
high activity against various strains of the yeast-like Candida fungus,
comparable to the activity commercial drug fluconazole.
10
0
In the presence of 3 methylene units (group IV), compounds with
methyl-, fluoro- and chloro-substituents, respectively, exhibited
IVa
IVc
IVb
maximum activity ( MIC 0.06–0.25 μg/ml), which slightly decreases
Fig. 2. Histogram MIC value (µg/mL) comparison of activity compounds IVa-c
against different fungi: 1 – C. parapsilosis ATCC 22019, 2 – C. utilis 84, 3 – C.
glabrata 61L. 4 – C. tropicalis 3019, 5 – C. krusei 432M, 6 – C. albicans ATCC
24433, 7 – C. albicans CBS 8837, 8 – Cryptococcus neoformans, 9 – A. Niger 37a,
10 – C. albicans 604M.
when the central hydrogen atom is replaced by hydroxyl (group III, MIC
2.0–8.0 g/ml). A reduction in the number of methylene units to 2
(group V) also had some negative effect on the microbiological activity
of the C. parapsilosis strain, remaining rather high (MIC 0.5–1.0 g/ml).
μ
μ
5

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Bioorganic & Medicinal Chemistry Letters 40 (2021) 127944
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The compounds can be arranged in the following order of increasing
biological activity against most of the fungus strains studied: IVa
(methyl-), IVc (chloro-) and IVb (fluoro-). Thus, by synthesizing hybrid
compounds based on a triazole group, a thiazolo-pyrimidine fragment
and a phenyl radical with halogen atoms, we were able to obtain new
antifungal substances with a wide spectrum of biological activity, which
can be used for further modifications.
8
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using the molecular hybridization approach. An analysis has been done
made of the effect produced by the linker structure and chemical nature
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alkylpiperazinyl linker exhibited strong in vitro antifungal activity,
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albicans CBS 8837, C. albicans 604M, C. utilis 84, C. tropicalis 3019, C.
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ejmech.2016.02.031.
Declaration of Competing Interest
17 Brito AF, Moreira LKS, Menegatti R, Costa EA. Piperazine derivatives with central
pharmacological activity used as therapeutic tools. Fund Clin Pharmacol. 2019;33:13.
https://doi.org/10.1111/fcp.12408.
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.
18 Rathi AK, Syed R, Shin HS, Patel RV. Piperazine derivatives for therapeutic use: a
patent review (2010-present). Expert Opin Ther Pat. 2016;26:777. https://doi.org/
10.1080/13543776.2016.1189902.
19 Heeres J, Meerpoel L, Conazoles LP. Molecules. 2010;15:4129. https://doi.org/
10.3390/molecules15064129.
Acknowledgements
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20 Pliska V. Lipophilicity in Drug Action and Toxicology. Chichester: John Wiley & Sons;
This work was supported by the grant of Russian Science Foundation
No. 19-13-00017.
2008.
21 Fromtling RA, Castaer J, Serradell MN. Fluconazole. Drugs Fut. 1985;10:982.
22 Gewald K. Reaktion von methylenaktiven nitrilen mit senfolen und schwefel. J Prakt
Chem. 1966;32:26. https://doi.org/10.1002/prac.19823240611.
23 Fahmy H, Sherif A, Rostom F, Saudi MN, Zjawiony KJ, Robins DJ. Synthesis and in
vitro evaluation of the anticancer activity of novel fluorinated thiazolo[4,5-d]
pyrimidines. Arch Pharm. 2003;336:216.
We thank “The Upper Volga Region Centre of Physicochemical
Research” for the technical assistance.
Appendix A. Supplementary data
24 Ombrato R. Preparation of fused heterocyclic compounds as antibacterial agents.
PCT, 2017211760, 20174.
25 Blokhina S, Ol’khovich M, Sharapova A, Perlovich G. Experimental investigation of
fluconazole: Equilibrium solubility and sublimation. J Chem Thermodyn. 2020;151:
1062. https://doi.org/10.1016/j.jct.2020.106243.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127944.
26 Pinal R. Effect of molecular symmetry on melting temperature and solubility. Org
Biomol Chem. 2004;2:2692. https://doi.org/10.1039/B407105K.
27 Alimuddin M, Grant D, Bulloch D, Lee N, Peacock M, Dahl R. Determination of logD
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