Article
Novel 1,2,3-Triazole Derivatives as Mimics of Steroidal
System—Synthesis, Crystal Structures Determination,
Hirshfeld Surfaces Analysis and Molecular Docking
Mateusz Das´ko 1,
*
, Anna Dołe˛ga 1 , Magdalena Siedzielnik 1, Karol Biernacki 2 , Olga Ciupak 2,
Janusz Rachon 2 and Sebastian Demkowicz 2
1
Department of Inorganic Chemistry, Faculty of Chemistry, Gdan´sk University of Technology, Narutowicza
11/12, 80-233 Gdan´sk, Poland; anna.dolega@pg.edu.pl (A.D.); m.siedzielnik@gmail.com (M.S.)
Department of Organic Chemistry, Faculty of Chemistry, Gdan´sk University of Technology, Narutowicza
11/12, 80-233 Gdan´sk, Poland; karol.biernacki@pg.edu.pl (K.B.); olgaciupak@gmail.com (O.C.);
januszrachon@gmail.com (J.R.); sebastian.demkowicz@pg.edu.pl (S.D.)
2
*
Correspondence: mateusz.dasko@pg.edu.pl
Abstract: Herein, we present the synthesis and crystal structures determination of five 4-(1-phenyl-
1H-1,2,3-triazol-4-yl)phenol derivatives containing halogen atoms, 6a , which may be used as an
–
e
excellent mimic of steroids in the drug development process. Good quality crystals obtained for all
of the synthesized compounds allowed the analysis of their molecular structures. Subsequently, the
determined crystal structures were used to calculate the Hirshfeld surfaces for each of the synthesized
compounds. Furthermore, results of our docking studies indicated that synthesized derivatives are
able to bind effectively to the active sites of selected enzymes and receptors involved in the hormone
biosynthesis and signaling pathways, analogously to the native steroids.
Citation: Das´ko, M.; Dołe˛ga, A.;
Siedzielnik, M.; Biernacki, K.; Ciupak,
O.; Rachon, J.; Demkowicz, S. Novel
1,2,3-Triazole Derivatives as Mimics
of Steroidal System—Synthesis,
Crystal Structures Determination,
Hirshfeld Surfaces Analysis and
Molecular Docking. Molecules 2021,
Keywords: triazoles; hormone analogs; drug design; crystal structures; Hirshfeld surface; molecu-
lar docking
1. Introduction
Academic Editors:
Triazoles are a class of compounds showing very interesting properties, e.g., hydrogen
Diego Muñoz-Torrero and
Cristobal De Los Rios
bond (HB) formation,
and therefore, they have been successfully used as scaffolds in the synthesis of antimicrobial,
antiviral, and antitumor agents [ ]. Importantly, they do not undergo hydrolysis under
π–π stacking interaction, large dipole moments, bioisosteric effects,
Received: 11 June 2021
Accepted: 1 July 2021
Published: 2 July 2021
acidic or basic conditions, and they withstand metabolic degradation, which is desired in
the design of new pharmaceuticals. The above advantages indicate that the derivatization
of the triazole ring may lead to compounds possessing interesting biological properties. For
example, the introduction of two additional phenyl rings with diverse substituents to the
1,2,3-triazole ring should allow the production of 4-(1-phenyl-1H-1,2,3-triazol-4-yl)phenol
derivatives demonstrating similarities to some natural compounds, e.g., hormones.
The hormone signaling pathway is a well-established target for the development of
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hormone-dependent cancer drugs (e.g., breast cancer) [
2]. For example, one of the clinically
used drugs—Tamoxifen (Figure 1) acts as a selective estrogen receptor modulator (SERM).
1
On the other hand, chemotherapeutics, which may influence the hormone formation
process, are of high therapeutic importance. The biosynthesis of active steroids (e.g.,
estradiol (E2) and androstenediol (Adiol)) in cancer tissues mainly depends on three
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Attribution (CC BY) license (https://
4.0/).
enzymatic pathways: aromatase (AROM), 17
β-hydroxysteroid dehydrogenase (17
β-HSD)
and steroid sulfatase (STS) [ ]. For example, currently used Letrozole
2
and Anastrozole 3
(Figure 1) block the conversion of androgens to estrogens via the inhibition of the AROM
complex. In light of recent research indicating that the disorders in sulfation/desulfation
processes may be responsible for numerous pathologies [4], the other enzyme implicated
in the steroidogenesis process—STS—is becoming a new, interesting molecular target in