Synthesis, characterization, theoretical studies and antimicrobial activity of novel 1-(2?hydroxy-4-propoxy-3-propylphenyl)ethanones bearing thiotetrazole

Article abstract of DOI:10.1016/j.molstruc.2021.130818

We report herein a joint experimental and theoretical investigation on the novel 1-(2-hydroxy-4-propoxy-3-propylphenyl)ethanone bearing 1-propyl-1H-tetrazol-5-thiol and 2-propyl-2H-tetrazole-5-thiol pharmacophores. In the experimental studies, 1-[4-(3-((1

Full text of DOI:10.1016/j.molstruc.2021.130818

Journal Pre-proof
Synthesis, characterization, theoretical studies and antimicrobial
activity of novel 1-(2-hydroxy-4-propoxy-3-propylphenyl)ethanones
bearing thiotetrazole
Ali Disli , Esin Eylem Yucesoy , Yusuf Erdogdu ,
¨
Mehmet Tahir Gulluoglu , Ali Oztu¨rk , Gulay Dilek
PII:
S0022-2860(21)00951-0
DOI:
Reference:
https://doi.org/10.1016/j.molstruc.2021.130818
MOLSTR 130818
To appear in:
Journal of Molecular Structure
Received date:
Revised date:
Accepted date:
3 March 2021
11 May 2021
30 May 2021
Please cite this article as: Ali Disli , Esin Eylem Yucesoy , Yusuf Erdogdu , Mehmet Tahir Gulluoglu ,
¨
Ali Oztu¨rk , Gulay Dilek , Synthesis, characterization, theoretical studies and antimicrobial activity of
novel 1-(2-hydroxy-4-propoxy-3-propylphenyl)ethanones bearing thiotetrazole, Journal of Molecular
Structure (2021), doi: https://doi.org/10.1016/j.molstruc.2021.130818
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Synthesis, characterization, theoretical studies and antimicrobial activity of
novel 1-(2-hydroxy-4-propoxy-3-propylphenyl)ethanones bearing
thiotetrazole
Ali Dislia,*, Esin Eylem Yucesoya, Yusuf Erdogdub, Mehmet Tahir Gulluogluc, Ali Öztürkd,
Gulay Dileke,*
aDepartment of Chemistry, Faculty of Science, Gazi University, 06500 Teknikokullar, Ankara, Turkey
bDepartment of Physics, Faculty of Science, Gazi University, 06500 Teknikokullar,
Ankara, Turkey
cDepartment of Electric and Electronic Engineering, Faculty of Engineering, Harran University,
Sanliurfa, Turkey
dDepartment of Medical Microbiology, Nigde Omerhalis Demir University, Nigde, Turkey
eDepartment of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Zonguldak Bulent Ecevit
University, 67600 Esenkoy, Zonguldak, Turkey
*
Corresponding
author:
E-mail
address:
adisli@gazi.edu.tr
(A.
Disli),
gulaydilekcelik@hotmail.com (G. Dilek)
Highlights
 Two
novel
1-(2-hydroxy-4-propoxy-3-propylphenyl)ethanones
bearing
thiotetrazole were synthesized.
 Their structures were characterized by various spectroscopic techniques.
 DFT computational studies were carried out to understand the molecular structure,
vibrational and NMR spectra of the compounds.
 The compounds prefer to adopt Gauche-Gauche (GG) conformation.
 Antimicrobial activities of the compounds were evaluated.
 Both compounds showed a wide range of antimicrobial activity and inhibited all
bacteria and fungi tested.
Graphical Abstract
ABSTRACT

We report herein a joint experimental and theoretical investigation on the novel 1-(2-hydroxy-
4-propoxy-3-propylphenyl)ethanone bearing 1-propyl-1H-tetrazol-5-thiol and 2-propyl-2H-
tetrazole-5-thiol pharmacophores. In the experimental studies, 1-[4-(3-((1-propyl-1H-tetrazol-
5-yl)thio)propoxy)-2-hydroxy-3-propylphenyl]ethanone and 1-[4-(3-((2-propyl-2H-tetrazol-5-
yl)thio)propoxy)-2-hydroxy-3-propylphenyl]ethanone were synthesized and characterized by
1
ATR-FTIR, H-NMR, 13C-APT, and HRMS. In the theoretical studies, the most stable
conformations, vibrational and NMR spectra of these compounds were predicted by Quantum
chemical calculations. Quantum chemical calculations were performed using the B3LYP
functional with 3-21G, and 6-311++G(d,p) basis sets. All quantum chemical calculations were
utilized Gaussian 16 software. While torsional barriers of the compounds were determined by
B3LYP/ 3-21G, their geometry optimizations were performed by B3LYP functional with 3-
21G, and 6-311++G(d,p) basis sets. The harmonic vibrational frequencies, potential energy
distribution (PED) and infrared intensities were predicted using the B3LYP/6-311++G(d,p).
Theoretically predicted vibrational frequencies were compared with experimental results.
Predicted NMR chemical shifts were obtained by the GIAO method using the B3LYP/6-
311++G(d,p). The 1H and 13C experimental chemical shifts are consistent with the theoretical
NMR chemical shift values. Antimicrobial activities of the title compounds were investigated
against five bacterial strains (Staphylococcus aureus, Staphylococcus epidermidis,
Escherichia coli, Pseudomonas aeruginosa, Stenotrophomonas maltophilia) and two fungal
strains (Candida albicans, Aspergillus fumigatus). The compounds showed good
antimicrobial activity and inhibited all tested bacteria and fungi.
Keywords: Thiotetrazole, Alkyl tetrazole, Antimicrobial activity, Conformational analysis,
DFT.
1. Introduction
Heterocyclic compounds constitute an intensive research area in organic chemistry.
These cyclic compounds have found many applications in technology and life sciences [1, 2].
Among heterocyclic compounds, tetrazoles (CH2N4) have great attention by researchers. The
number of patents and publications on syntheses, properties, and applications of tetrazoles
increases each day [3-7]. Their nitrogen-rich, multi-electron, conjugated, and planar structural
features ensure them to be used in numerous fields [8]. Tetrazoles are used for their explosive

and combustive properties [9]. They produce non-toxic, high-temperature reaction products.
Therefore, tetrazoles are used as a component of gas generators [10]. Moreover, tetrazole-
based energetic compounds are effective compounds for inflating airbags [11]. The ability of
the tetrazoles to form stable complexes with metals is used to protect metals against corrosion
[12, 13]. Tetrazoles are used in photography as stabilizers [14]. Besides, they are applied in
the structural framework of pesticides, herbicides, fungicides, and plant growth regulators in
agriculture [15-17]. However, the most prominent application area of tetrazoles is in
pharmaceutical chemistry [8]. Since they are flexible ligands, they can easily adapt to
different binding sites of the targets [18, 19]. 1,5-Disubstituted tetrazoles mimic cis-amide
conformation [20]. Tetrazole ring is the most commonly used carboxylic acid surrogate [21].
The incorporation of tetrazole into a drug molecule enhances metabolic stability, hence the
efficacy and the half-life of the drug increase [22, 23]. Moreover, bioisosteric replacement of
carboxylic acid with tetrazole reduces the toxicity of the drug and increases its
pharmacokinetic profile and lipophilicity [24]. For all these reasons, the tetrazole ring is the
component of many drugs.
Tetrazole and its derivatives demonstrate a wide range of biological activities. They
show anticancer, nootropic, antitubercular, analgesic, anticonvulsant, antihistaminic,
antidiabetic, antihypertensive, antihyperlipidemic, antibiotic, antiviral, and antifungal
properties [25]. At present, as stated by Drug Bank, 64 drugs have tetrazole rings in their
structures and 23 out of them have been approved by the FDA [24]. The first orally active
LTD4 receptor antagonist tomelukast is a tetrazole-derived pharmaceutical agent showing
efficacy in patients with asthma [23]. Losartan, cardesartan, irbesartan, olmesartan, valsartan,
forasartan, tasosartan are all angiotensin II receptor antagonists containing tetrazole fragment
in their structures [26]. Compounds containing N-substituted thiotetrazole, such as 5-((3-((1-
benzyl-1H-tetrazol-5-yl)thio)propyl)thio)-4-(2,5-dichlorophenyl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (a), 2-chloro-5-((1-ethyl-1H-tetrazol-5-yl)thio)-4,6-dimethoxypyrimidine (b), 2-
[(1-methyl-1H-tetrazol-5-yl)thio]-1-phenylethanone (c), have been proved to exhibit
antimicrobial activity (Fig. 1) [27-30]. Cefotiam, cefamandole, cefmenoxime, cefmetazole,
cefpiramide, ceforanide, cefonicid, cefoperazone, cefotetan, and latamoxef are FDA-approved
drugs that contain N-substituted thiotetrazoles in their structures. These agents are all used in
clinics to treat bacterial infections [24, 30].
 Position of Fig. 1

The present work details theoretical and experimental studies of two novel compounds
containing N-alkyl substituted thiotetrazole. Compounds. 4a and 4b were synthesized and the
structures were characterized by HRMS, 1H- and 13C-NMR, and FT-IR spectroscopy. We also
report the theoretical results of a systematic study of geometrical structure, vibrational
spectra, and NMR spectra of 4a and 4b by Density Functional Theory (DFT) calculations.
Finally, antifungal and antibacterial activities of 4a and 4b were studied against five bacterial
and two fungal strains.
2. Materials and methods
The chemicals were acquired from Acros Organics, Merck, and Aldrich and used
without additional purification. NMR spectra were recorded in CDCl3 on Bruker Avance
DPX-300 NMR spectrometer. ATR-FTIR spectra were obtained on a Thermo Nicolet 6700
ATR spectrometer. Mass spectra were measured on Waters LCT Premier XE LTOF. Melting
points were determined by Stuart SMP-30 apparatus and were uncorrected. Merck Silica Gel
60 (0.63-0.200 mm) was used for column chromatography.
2.1. Computational procedure
Theoretical predictions were utilized by the Gaussian 16 software [31]. The function
used in all calculations was DFT/B3LYP [32-34]. Basis sets used with this function were 3-
21G and 6-311++G(d,p). While all basis sets were used for the optimization, the 6-
1
311++G(d,p) basis set was used for the spectroscopic (vibrational and H and 13C NMR)
calculations. The vibrational assignments were determined by Potential Energy Distribution
(PED). The theoretical NMR shift values of the title compounds were obtained by using
Gauge Independent Atomic Orbital (GIAO) method. The NMR chemical shifts were
calculated for chloroform solution using the IEF-PCM model. The results of the calculated 1H
and 13C NMR shifts were matched with the experimental ones. The identification and
characterization of the compounds were done using this matching. Absolute isotropic
magnetic shielding constants were converted into chemical shifts. This conversion was done
relative to tetramethylsilane (TMS), the compound used as a standard [35 -36].
2.2. Experimental

2.2.1. Synthesis of 1-[4-(3-chloropropoxy)-2-hydroxy-3-propylphenyl]ethanone 1
A mixture of 2′,4′-dihydroxy-3′-propylacetophenone (1.94 g, 0.01 mol), KI (0.83 g,
0.005 mol), 1-bromo-3-chloropropane (6.30 g, 0.04 mol), and K2CO3 (4.15 g, 0.03 mol) in 50
mL acetone was stirred and heated under reflux for 24 h. The solution was filtered out and the
filtrate was concentrated under vacuum. The crude product was purified by column
chromatography on silica gel (ethyl acetate-petroleum ether, 1:5). Yield 68%, mp 61-62 °C.
(lit. [37] mp 61.7 °C).
2.2.2. Synthesis of 1-[4-(3-thiocyanatopropoxy)-2-hydroxy-3-propylphenyl]ethanone 2
Compound 1 (0.93 g, 0.0032 mol) and ammonium thiocyanate (0.33 g, 0.0043 mol)
o
were stirred and heated to 75 C for 24 h in DMF (25 mL). The solution was cooled to
ambient temperature. After filtering out NH4Cl salt formed, the filtrate was acidified with
10% HCl to pH 1-2 and poured on ice water. It was then extracted with ethyl acetate (4 x 25
mL). The organic layers were combined, dried over Na2SO4, and filtered. The filtrate was
concentrated under vacuum and the crude product was purified by column chromatography on
silica gel (1:5 ethyl acetate-petroleum ether). Yield 45%, yellow viscous oil, bp 210 °C. (lit.
[38, 39] bp 210 °C).
2.2.3. Synthesis of 1-[4-(3-((1H-tetrazol-5-yl)thio)propoxy)-2-hydroxy-3-
propylphenyl]ethanone 3
To the solution of triethylammonium chloride (1.51 g, 0.011 mol) in 50 mL toluene,
sodium azide (0.72 g, 0.011 mol) was added in small portions. Compound 2 (0.84 g, 0.003
mol) dissolved in toluene (30 mL) was added dropwise. The mixture was heated with stirring
under reflux for 23 h. The reaction mixture was allowed to cool to room temperature. 20 mL
distilled water was added. After the separation of aqueous layer, toluene layer was washed
with water (3 x 5 mL). Aqueous layers were combined and acidified with 10% HCl to pH 3-4.
The solid formed was filtered and washed with water [40, 41]. Yield 95%, mp 130-132 °C
1
3
(lit. [38] mp 131-133 °C). H-NMR (300 MHz, CDCl3) δ ppm: 0.90 (t, JHH = 7.3 Hz, 3H,
CH3), 1.40-1.60 (m, 2H, CH2), 2.20-2.40 (m, 2H, CH2), 2.56 (s, 3H, CH3), 2.64 (t, 3JHH = 7.3
Hz, 2H, CH2), 3.50 (t, 3JHH = 5.7 Hz, 2H, CH2), 4.18 (t, 3JHH = 5.7 Hz, 2H, CH2), 6.43 (d, 3JHH

= 8.9 Hz, 1H, Ar-H), 7.58 (d, 3JHH = 8.9 Hz, 1H, Ar-H), 12.73 (s, 1H, OH). FT-IR υmax cm-1:
3600-3500 (-OH), 3300-3100 (N-H), 3091 (Ar-H), 2924 (-C-H), 1626 (C=O).
2.2.4.
Synthesis
of
1-[4-(3-((1-propyl-1H-tetrazol-5-yl)thio)propoxy)-2-hydroxy-3-
propylphenyl]ethanone 4a and 1-[4-(3-((2-propyl-2H-tetrazol-5-yl)thio)propoxy)-2-
hydroxy-3-propylphenyl]ethanone 4b
1-Boromopropane (1.97 g, 0.016 mol) and K2CO3 (2.21 g, 0.016 mol) were added to
the solution of compound 3 (2.69 g, 0.008 mol) in 25 mL DMF. The mixture was heated with
stirring at 80oC for 21-23 h. When the reaction was completed, it was allowed to cool to room
temperature. The solution was poured into ice water and extracted with ethyl acetate (4 x 25
mL). The organic layers were combined, dried over Na2SO4, and filtered. The filtrate was
concentrated under vacuum and the crude product was purified by column chromatography on
silica gel (1:5 ethyl acetate-petroleum ether) to give two isomers, 4a and 4b.
1-[4-(3-((1-propyl-1H-tetrazol-5-yl)thio)propoxy)-2-hydroxy-3-propylphenyl]ethanone 4a
1
Viscous liquid. H-NMR (300 MHz, CDCl3) δ ppm: 0.90-1.00 (m, 6H, 2CH3), 1.35-
3
1.65 (m, 2H, CH2), 2.02 (sextet, JHH = 7.1 Hz, 2H, CH2), 2.20-2.40 (m, 2H, CH2), 2.56 (s,
3
3H, CH3), 2.64 (t, 3JHH = 7.1 Hz, 2H, CH2), 3.40 (t, JHH = 7.0 Hz, 2H, CH2), 4.18 (t, 3JHH
=
3
3
5.8 Hz, 2H, CH2), 4.51 (t, JHH = 7.1 Hz, 2H, CH2), 6.43 (d, JHH = 9.0 Hz, 1H, Ar-H), 7.58
3
(d, JHH = 9.0 Hz, 1H, Ar-H), 12.73 (s, 1H, OH). 13C-APT (75 MHz, CDCl3) δ ppm: 10.8
(CH3), 14.2 (CH3), 21.9 (CH2), 22.6 (CH2), 24.3 (CH2), 26.2 (CH3), 28.8 (CH2), 29.3 (CH2),
54.8 (CH2), 65.9 (CH2), 102.6-163.3 (C Ar), 202.9 (C=O). FT-IR υmax cm-1: 3020 (Ar-H),
2990 (-C-H), 1630 (-C=O). HRMS (ESI TOF-MS): m/z calculated for C18H27N4O3S [M+H]+:
379.1804; Found: 379.1625.
1-[4-(3-((2-propyl-2H-tetrazol-5-yl)thio)propoxy)-2-hydroxy-3-propylphenyl]ethanone 4b
1
Viscous liquid. H-NMR (300 MHz, CDCl3) δ ppm: 0.90-1.00 (m, 6H, 2CH3), 1.52-
3
1.62 (m, 2H, CH2), 1.92 (sextet, JHH = 7.0 Hz, 2H, CH2), 2.35-2.45 (m, 2H, CH2), 2.57 (s,
3
3H, CH3), 2.65 (t, 3JHH = 7.0 Hz, 2H, CH2), 3.55 (t, JHH = 7.0 Hz, 2H, CH2), 4.18 (t, 3JHH
=
3
3
7.0 Hz, 4H, 2CH2), 6.44 (d, JHH = 9.0 Hz, 1H, Ar-H), 7.60 (d, JHH = 9.0 Hz, 1H, Ar-H),
13
12.75 (s, 1H, OH). C-APT (75 MHz, CDCl3) δ ppm: 10.9 (CH3), 14.2 (CH3), 22.0 (CH2),
22.4 (CH2), 24.4 (CH2), 26.2 (CH3), 29.0 (CH2), 29.6 (CH2), 48.9 (CH2), 65.9 (CH2), 102.5-

162.3 (CAr), 202.9 (C=O). FT-IR υmax cm-1: 3050 (Ar-H), 2940 (-C-H), 1640 (-C=O). HRMS
(ESI TOF-MS): m/z calculated for C18H27N4O3S [M+H]+: 379.1804; Found: 379.1674.
2.3. Antimicrobial testing method
Minimum inhibitory concentration (MIC) and minimum bactericidal/fungicidal
concentration (MBC/MFC) values were determined using the broth microdilution method
recommended in European Committee on Antimicrobial Susceptibility Testing (EUCAST)
guide [42]. The clinical isolates (Staphylococcus epidermidis, Staphylococcus aureus,
Escherichia coli, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Candida
albicans, and Aspergillus fumigatus) used in this study were obtained from Clinical
Microbiology Laboratory (Nigde Omer Halisdemir University, Nigde, Turkey). No ethical
approval was required to use the clinical isolates in this study since isolates were obtained
from clinical samples during routine microbiology investigations and were not part of a
clinical trial.
Final suspensions of 3×105 cells/mL for bacteria and 1,5×105 cells/mL for fungi were
prepared from 24-48 hour-cultures. 100 µL of broth media (Mueller-Hinton Broth for bacteria
and RPMI 1640 2% glucose for fungi) were added to all wells in a 96-well flat-bottom plate.
100 µL of the last inoculums of bacteria and fungi were added to all wells (except for 11th and
12th control wells). Serial dilutions of the compounds were prepared at 256-0.5 µg/mL. The
microplates were incubated for 24-48 hours at 37oC. Gentamicin, vancomycin, imipenem
were used as reference antibacterial agents, and fluconazole was used as a reference
antifungal agent under similar conditions for comparison. Serial dilutions of the antibacterial
and antifungal agents were also prepared at 256-0.5 µg/mL. The 11th well in the plate was
used for sterility control (broth only) and the 12th well was used for growth control (broth and
inoculum).
3. Results and discussion
3.1. Chemistry
The synthetic pathway to compounds 4a and 4b is presented in Scheme 1. Compound
1 was synthesized through the reaction of 2′,4′-dihydoxy-3′-propylacetophenone with 1-
bromo-3-chloropropane, K2CO3, and KI in acetone, according to previous literature [37]. 1-

[4-(3-thiocyanatopropoxy)-2-hydroxy-3-propylphenyl]ethanone 2 was prepared by refluxing
the compound 1 with ammonium thiocyanate in DMF [38, 39]. The reaction of compound 2
with sodium azide and triethylamine hydrochloride in toluene resulted compound 3. –CN
group on the side chain was converted into a tetrazole through cycloaddition of sodium azide.
1
The product was identified using melting point, H-NM, and FT-IR spectra. The IR spectrum
shows a characteristic stretching absorption band at 3100-3300 cm-1, indicative of NH bond of
tetrazole ring. Compound 3 was then allowed to interact with 1-bromopropane in the presence
of K2CO3 in DMF. Alkylation of tetrazole yielded two isomers, 1,5- and 2,5-disubstituted
thiotetrazole derivatives. 1,5-disubstituted (4a) and 2,5-disubstituted (4b) thiotetrazole
derivatives were separated and purified using column chromatography. The structures of 4a
and 4b were estimated by 1H-, 13C-NMR, FT-IR, and MS-spectra. All the data confirm the the
13
basic chemical structures of 4a and 4b. In C-APT spectra, the carbon atom of the tetrazole
ring was observed at 162 ppm. Disappearance of stretching absorption band at 3100-3300 cm-
1
has also been attributed to the formation of the target compounds. 4a and 4b were reported
for the first time.
 Position of Scheme 1
3.2. Rotational barriers and molecular geometries
The starting point for further calculations is to determine the most stable conformer for
compounds under investigation. Calculations with the most stable conformer are required to
obtain meaningful results. This is not an easy task in the absence of experimental structural
information, especially when dealing with complex compounds. We do not have any
experimentally structural parameters for the compounds studied. Therefore, a systematic
study method was adopted for the theoretical calculation of the compounds under study. First,
the binding characteristics of the trimethylene chain were determined (Fig. S1). Then, the
possible conformations of Ring-1 and Ring-2 were decided. Based on all these data, the initial
geometries of both 4a and 4b were created. These compounds are composed of Ring 1 and
Ring 2-a or Ring 1 and Ring 2-b, bridged with a trimethylene chain. If the compound is
composed of Ring 1, Ring 2-a, and the trimethylene chain, it becomes 4a. If the compound is
composed of Ring 1, Ring 2-b and trimethylene chain, it becomes 4b. All detailed discussions
are given in the following section.

The title compounds have exhibited four popular conformations (Trans-Trans (TT),
Trans-Gauche (TG), Gauche-Gauche (GG), and Gauche-Gauche (GG)) resulting from free
rotation about the single C-C-C bonds of the trimethylene chain [43]. Such four
conformations were also distinguished from dihedral angle of Ring-1 and Ring-2. Therefore,
four specific structures of the title compounds were achieved. In the trimethylene chain, only
one of the atoms denoted by 1, 2, and 3 is an oxygen atom. Similarly, one of the atoms
denoted by 1, 2, and 3 is a sulfur atom. Ring-1 is attached to the trimethylene chain with one
of the atoms indicated by 1, 2, or 3. Ring-2 is attached to the trimethylene group with one of
the atoms indicated by 1, 2, or 3. Ring-1 and Ring-2 are given in Fig. S2. Ring-1 has four
conformations due to the orientation of the acetyl and OH groups. In Ring-1, the oxygen atom
indicated by X is the atom attached to the trimethylene group. In the trimethylene group, this
atom is marked by 1, 2, or 3. While 4a has Ring-2a, 4b contains Ring-2b. Based on the
information explained above, 16 initial geometries were determined for each compound (Fig
S3).
To generate all possible conformations, the potential energy surface (PES) analysis for
4a and 4b was performed at the B3LYP/3-21 G level of theory. The potential energy surface
(PES) scan for all initial geometries was carried out around the C-O (C1-O10-C11-C12) and C-S
(C7-S37-C38-N39) bonds by varying the torsion angle from 0o to 360o in steps of 10o (Fig. S4).
As a result of PES scan, it was determined that there were 137 different geometries for 4a and
149 different geometries for 4b. All critical points were taken into account when determining
these geometries. Critical points were the points where the PES curve changed its direction.
To determine geometries with the same energy, these geometries from the PES results of 4a
and 4b were re-optimized at the B3LYP/3-21G level of theory. In the last step, geometries
with relative energy less than 10 eV were re-optimized at the B3LYP / 6-311++G (d, p) level
of theory (Table 1 and Table 2). While the most stable state of 4a was the geometry numbered
118, the most stable state of 4b was the geometry numbered 111. However, further
calculations were made on these optimized structures shown in Figs. 2 and 3.


Position of Table 1
Position of Table 2
 Position of Fig. 2
 Position of Fig. 3

3.3. Molecular geometries
The most stable geometry of trimethylene chain was determined as Gauche-Gauche
conformation. The C7-S37-C38-N39 and C1-O10-C11-C12 dihedral angles were founded about 0
for each compound. It has been determined that the acetyl group and the OH group have the
same orientation. The most important difference between the two compounds is the position
where the propyl group is attached to the tetrazole ring. When the propyl group is connected
to the Carbon-40, compound 4a is formed. When the propyl group is attached to the Carbon-
42, compound 4b is formed. There is no imaginary frequency in the results of vibrational
analysis. This indicates that all the computations converge to true minimum energy. The
calculated results of the optimized bond lengths, dihedral angles, and bond angles of 4a and
4b are presented in Table S1. The atoms in the structure of 4a and 4b are indicated by
numbers. The molecular structures of 4a and 4b, in which the atoms are represented by
numbers, are shown in Fig. 4.
 Position of Fig. 4
3.4. Vibrational Analysis
Both compounds possess C1 point-group symmetry. They have 52 atoms
(C18H26N4O3S) with 150 normal modes. All the vibrations are active in IR spectra. The
experimental Fourier Transform Infrared (FT-IR) spectra of both compounds are given in Fig.
5. The observed and predicted wavenumbers, their relative infrared intensities, potential
energy distributions of 4a and 4b are listed in Tables 3 and 4.
 Position of Fig. 5
 Position of Table 3
 Position of Table 4
The potential energy distribution (PED) calculations were carried out by using the
Gaussian 16 software package. The PED contributions lower than 10% were not considered.
The theoretical vibrational wavenumbers were calibrated with the scaling factor to compare
the observed values with the calculated values and to minimize the difference between them.
The authors scaled the calculated frequencies by 0.960 in the high wavenumbers region and

0.988 in the low wavenumbers region (below 1800 cm-1) for the B3LYP/6-311++G(d,p) level
of theory [44]. The assignments for vibrational modes are obvious; therefore only a brief
analysis is given here. A general analysis of the selected modes is as follows.
The stretching modes of the CH, CH2 and CH3 groups with about 80% PED
contributions were predicted in the region of 125-149 mode numbers by the DFT. The
vibrational modes in these mode numbers were detected at 2867, 2927, 2956 cm-1 for 4a and
2854, 2868, 2925, 2958 cm-1 for 4b in the infrared spectra. The peaks appeared at 2867 cm-1
(4a) and 2869 cm-1 (4b) were assigned to the CH3 stretching vibrations of the propyl group on
Ring-1. CH2 stretching vibrations of trimethylene unit and propyl group of Ring-2 were
measured experimentally at 2956 /2958 cm-1 and 2927 /2925 cm-1 for 4a/4b in the infrared
spectra. The CH2 stretching mode of the trimethylene group was located at 2854 cm-1 in the
infrared spectrum of 4a. The counterpart of this peak could not be observed in the infrared
spectrum of 4b.
The mode number 124 highlighted in the infrared spectra is associated with the C=O
stretching mode of Ring-1. It is located at 1677 cm-1 (4a) and 1670 cm-1 (4b) in the infrared
spectra. These peaks were predicted at 1649 cm-1 (4a) and 1648 cm-1 (4b) by DFT
calculations. Also, PED determined the contribution as mixed with CO, CC stretching and
CCC, CCH bending.
All observed vibrational modes and their theoretical equivalences are given in Tables
3 and 4. Based on the consistency between the calculated and observed results, the
assignments of fundamental vibrational modes of the title compounds were investigated. The
difference between the observed and scaled wavenumber values in most of the fundamentals
is very small. Comparison between the calculated and experimental vibrational spectral data
indicates that DFT-based results are in good agreement with the experimental findings.
Moreover, the vibrational modes of 4a are very similar to those of 4b. The experimental and
theoretical vibrational modes are very similar in both their assignments and numerical values.
3.5.
NMR Spectra
1
13
Theoretical H NMR and C NMR chemical shifts of 4a and 4b were determined by
using the GIAO method. These calculations were completed using the B3LYP/6-311++G(d,p)
level of theory in the most stable structure for each compound. The results of observed and

calculated 1H and 13C nuclei are compared in Table 5. Experimental 1H and 13C NMR spectra
are given in Fig. 6.
 Position of Fig. 6
 Position of Table 5
The signals of the aromatic carbon atoms are reported in the range of 102.6-163.3 ppm
in 13C NMR. If nuclear magnetic spectra of aromatic carbons of the title compounds are
divided into two parts according to chemical shifts, the first part is located in a region above
140 ppm. C24, C11, and C16 atoms are more deshielded because these atoms are attached to an
electronegative oxygen atom. The experimental signal of the C24 atom was observed at 202.9
ppm. The experimental signals of C11 and C16 were detected about 162 ppm. C38 atom is
connected to the different electronegative atoms on both sides (nitrogen and sulfur atoms). 13C
NMR signals of the C38 were observed at 162.0 ppm for 4a and 163.3 ppm for 4b.
13
The second part is in the 100-140 ppm region. In this region, the C NMR signal of
the aromatic carbon atoms which are not bonded to the oxygen, nitrogen, and sulfur atoms
were detected. These atoms are C14, C13, C18, and C12. The experimental signals were
observed at 130.1 (C14), 118.2 (C13), 114.2 (C18), and 102.6 ppm (C12) for 4a.
The other part is in the region below 100 ppm. The trimethylene unit in the structure
of 4a and 4b has three carbon atoms (C1, C4, and C7 atoms). The 13C NMR signals of C4 and
C7 were detected at about 29 ppm for both compounds. The signal of C1 atom showed greater
downfield shift than those of C4 and C7 atoms because C1 atom is bonded to the
electronegative oxygen atom (O10). The largest chemical shift difference in carbon spectra
was determined at Carbon-43. The main difference between 4a and 4b was that the chemical
shift of C43 was observed at 54.8 ppm in 4a and 48.9 ppm in 4b. The chemical shifts of C44,
C21, C26, and C47 atoms of 4a were observed at 22.6, 21.9, 14.2, and 10.8 ppm, respectively.
As seen in Fig. 6 and Table 5, the nuclear magnetic carbon spectra and data of both
compounds are similar.
Protons of 4a were found to be between 12.73 and 0.90 ppm and the chemical shifts of
4b were obtained at 12.79-0.90 ppm. They were predicted at 12.86–0.85 ppm (for 4a) and
12.79-0.98 ppm (for 4b). H25 bonded to the oxygen atom was measured at 12.73 ppm (for 4a)
and 12.75 ppm (for 4b). The aromatic protons (H19 and H15) apeared at 7.58 ppm (H19 for 4a),

6.43 ppm (H15 for 4a), 7.60 ppm (H19 for 4b), and 6.44 ppm (H15 for 4b). CH2 protons
appeared between 4.51-1.54 ppm for 4a and 4.18-1.52 ppm for 4b. The signal of CH3 protons
in the propyl groups were observed between 0.90-1.00 ppm. CH3 protons on Ring-1 were
detected at 2.56 ppm (for 4a) and 2.57 ppm (for 4b). 1H and 13C NMR signals of 4a are very
similar to those of 4b. When the theoretical and experimental NMR spectra are compared, it
is seen that the experimental NMR signals are very similar to the theoretical ones.
3.6. Antimicrobial activity
The drugs containing N-substituted thiotetrazole moiety are used for the treatment of
bacterial infections [24-30]. Therefore, the compounds 4a and 4b were tested for their
antibacterial and antifungal activities. MIC and MBC/MFC values of 4a and 4b against
Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis), Gram-negative
(Escherichia coli, Stenotrophomonas maltophilia, Pseudomonas aeruginosa), and fungal
strains ( Candida albicans, Aspergillus fumigatus) were listed in Tables 6 and 7, respectively.
As shown in Tables 6 and 7, 4a and 4b inhibited all tested bacteria and fungi and they
displayed broad-spectrum antimicrobial activities with MIC values ranged between 4 and 64
µg/mL. Among 1,5- and 2,5-disubstituted thiotetrazole derivatives, 1-[4-(3-((2-propyl-2H-
tetrazol-5-yl)thio)propoxy)-2-hydroxy-3-propylphenyl]ethanone 4b, 2H-tautomeric form, was
found to be the most active antimicrobial member (MIC=4-16 µg/mL and MBC=32-64
µg/mL) and demonstrated strong impact on the strains tested. It even had better antibacterial
activity compared to imipenem, the reference drug.
In a study on the antimicrobial activity of N-substituted thiotetrazoles [27], 2-[(1-
methyl-1H-tetrazol-5-yl)thio]-1-phenylethanones displayed broad-spectrum fungicidal
activity (MIC=8-375 mg/mL) for selected strains, and showed comparable or even better
activity compared to ketoconazole, the reference drug. In this study, 4a and 4b possessed also
comparable or even better antifungal activity compared to fluconazole. They exhibited potent
fungicidal activity with MFC values within the concentration range of 32-64 µg/mL. The
activity of 4b (MFC=32 µg/mL) against C. albicans was found to be four times higher than
fluconazole.


Position of Table 6
Position of Table 7

4. Conclusions
To conclude, two novel N-substituted thiotetrazole derivatives were synthesized. A
systematic study method is adopted for the theoretical calculation of the title compounds. The
binding characteristic features of the trimethylene unit and the possible conformations of the
rings have been determined. According to this knowledge, the initial geometries of the
compounds were created. The potential energy surface (PES) of compounds was scanned. The
results of the PES of compounds determined 137/149 different geometries. According to the
results of PES, the most stable state of 4a/4b is the geometry numbered 118/111 and the most
stable geometry of both was Gauche-Gauche conformation. Comparison between the
theoretical and experimental vibrational spectral data indicates that DFT calculation results
are in good agreement with the experimental ones. Experimental and theoretical nuclear
magnetic carbon spectra of both compounds are similar. The largest chemical shift difference
in the Carbon-13 NMR spectra was detected at Carbon-43. This is the main difference
between 4a and 4b that can be determined experimentally. Antimicrobial activities of the
compounds were evaluated. Both showed a wide range of antimicrobial activity and inhibited
all bacteria and fungi tested. 4b was found to be the most active antimicrobial member. It
showed better antibacterial and antifungal activity compared to the reference drugs.
Acknowledgment
The Quantum Chemical calculations reported in this paper were fully performed at
Harran University High-Performance Computing Center (Harran HPC resources).
Author Statement
Ali Disli: Design of study, resorces, investigation, supervision the findings of this study
Esin Eylem Yucesoy: Investigation, synthesis, characterization of compounds
Yusuf Erdogdu: Computational studies, writing draft
Mehmet Tahir Gulluoglu: Conceptualization, software, validation.
Ali Öztürk: Investigation of antimicrobial activity, writing draft
Gulay Dilek: Investigation, interpretation, writing, review and editing
Declaration of interests

☒ 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.
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Fig. 1. Some thio-substituted tetrazole derivatives exhibiting antimicrobial activity
Fig. 2. The molecular structures of the optimized conformers of 4a
Fig. 3. The molecular structures of the optimized conformers of 4b
Fig. 4. Molecular structures of 4a and 4b
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Fig. S1. Molecular structure of trimethylene chain
Fig. S2. Molecular structures of Ring-1, Ring-2a, and Ring-2b

Fig. S3. The initial geometries of 4a
Fig. S4. Potential energy surfaces of 4a
Fig. S5. Potential energy surfaces of 4b
Scheme 1. The synthetic pathway to 4a and 4b
Table 1 Conformers obtained PES for 4a
B3LYP/3-21 G
Opt. Energy1
B3LYP/6-311 G(d,p)
Opt. Energy1
B3LYP/6-311++G(d,p)
B3LYP/cc-pVDZ
Opt. Energy1
Rel. Energy2
0.000
0.054
1.249
1.307
1.324
1.340
1.683
1.801
2.579
2.741
3.090
5.293
6.595
Rel. Energy2
0.000
0.000
2.634
0.730
0.730
2.634
2.281
4.267
2.782
1.691
1.374
6.561
6.469
Opt. Energy1
Rel. Energy2
Rel. Energy2
0.000
0.000
2.488
0.746
0.746
2.488
2.384
4.000
2.734
1.624
1.553
6.371
6.580
Conformer-118
Conformer-119
Conformer-93
Conformer-58
Conformer-55
Conformer-92
Conformer-121
Conformer-104
Conformer-62
Conformer-56
Conformer-17
Conformer-61
Conformer-20
-1536.15266929
-1536.15258282
-1536.15067868
-1536.15058582
-1536.15055903
-1536.15053334
-1536.14998801
-1536.14979975
-1536.14855938
-1536.14830193
-1536.14774435
-1536.14423402
-1536.14215940
-1544.74263997
-1544.74263997
-1544.73844209
-1544.74147734
-1544.74147735
-1544.73844209
-1544.73900530
-1544.73584014
-1544.73820719
-1544.73994468
-1544.74044996
-1544.73218386
-1544.73233161
-1544.76197302
-1544.76197302
-1544.75808885
-1544.76055731
-1544.76055731
-1544.75808885
-1544.75878338
-1544.75514400
-1544.75720810
-1544.75933897
-1544.75972504
-1544.75124796
-1544.75176179
0.000
0.000
2.437
0.888
0.888
2.437
2.002
4.285
2.990
1.653
1.411
6.730
6.408
-1544.50284182
-1544.50284182
-1544.49887734
-1544.50165258
-1544.50165258
-1544.49887734
-1544.49904313
-1544.49646772
-1544.49848466
-1544.50025324
-1544.50036619
-1544.49268924
-1544.49235522
1Optimized energies are in a.u.
2Relative energies are in k.cal/mol
Table 2 Conformers obtained PES for 4b
B3LYP/3-21 G
B3LYP/6-311 G(d,p)
B3LYP/6-311++G(d,p)
B3LYP/cc-pVDZ
Opt. Energy1
Rel. Energy2
Opt. Energy1
Rel. Energy2
Opt. Energy1
Rel. Energy2
Opt. Energy1
Rel. Energy2
Conformer-111
Conformer-112
Conformer-114
Conformer-62
Conformer-100
Conformer-96
Conformer-95
Conformer-19
Conformer-58
Conformer-57
-1536.15174938
-1536.15166069
-1536.14978655
-1536.14946899
-1536.14822978
-1536.14802560
-1536.14785713
-1536.14741442
-1536.14682153
-1536.14643212
0.000
-1544.74755903
-1544.74755903
-1544.74606790
-1544.74609619
-1544.74282976
-1544.74298703
-1544.74267819
-1544.74586243
-1544.74338226
-1544.74338224
0.000
-1544.76649147
-1544.76649148
-1544.76499300
-1544.76478723
-1544.76148942
-1544.76166500
-1544.76188753
-1544.76481225
-1544.76221637
-1544.76221637
0.000
0.000
0.940
1.069
3.139
3.029
2.889
1.054
2.683
2.683
-1544.50754856
-1544.50754858
-1544.50604770
-1544.50614497
-1544.50305840
-1544.50361146
-1544.50290204
-1544.50552048
-1544.50359199
-1544.50359198
0.000
0.056
0.000
0.000
1.232
0.936
0.942
1.431
0.918
0.881
2.209
2.968
2.818
2.337
2.869
2.471
2.442
3.063
2.916
2.720
1.065
1.273
3.092
2.621
2.483
3.337
2.621
2.483

Conformer-98
Conformer-21
Conformer-97
Conformer-24
Conformer-63
Conformer-25
-1536.14628369
-1536.14569317
-1536.14536487
-1536.14516589
-1536.14346237
-1536.13956673
3.430
3.800
4.006
4.131
5.200
7.645
-1544.74126268
-1544.74447169
-1544.74126269
-1544.74450816
-1544.74609619
-1544.73643123
3.951
1.937
3.951
1.914
0.918
6.983
-1544.75985954
-1544.76343291
-1544.75985954
-1544.76381013
-1544.75511561
-1544.75585052
4.162
1.919
4.162
1.683
7.138
6.677
-1544,50414320
-1544.50414320
-1544.50191199
-1544.50405186
-1544.49449098
-1544.49605638
2,137
2.137
3.537
2.194
8.194
7.211
1Optimized energies are in a.u.
2Relative energies are in k.cal/mol
Table 3 The vibrational spectral data of 4a
Exp.
561
Mode No. Freq
IIR
PED (%)
560
1.052
2.135
0.094
1.260
0.943
0.564
0.814
0.207
3.273
4.912
2.256
14.42
1.542
3.207
0.241
3.558
1.916
2.440
0.025
0.754
4.787
2.857
5.278
2.211
100
39
40
41
42
44
45
46
48
51
53
54
55
58
61
63
64
65
66
67
76
79
80
82
83
87
88
95
97
99
101
105
111
112

CCC(14%)+CCH(13%)+CCCC(13%)+CCCH(18%)
CCH(10%)+CCC(11%)+HCCH(12%)+CCCH(14%)+CCCC(14%)
567
566

597
598




CCCC(24%)+CCCH(16%)+CCCO(14%)
628
623
HCCH(21%)+CCCH(10%)
653
654
OCCC(20%)+CCCC(22%)+HCCC(24%)
NCNN(13%)+CNCH(11%)+CSCN(11%)+SCNC(10%)
676
677
684
681

CC(10%)+CCC(10%)+CCH(10%)+HCCH(15%)+CCCH(16%)
CCH(16%)+HCCH(44%)+CCCH(22%)
CCH(10%)+HCCH(14%)+HCCC(11%)
729
736
750
750

783
779

OCCH(10%)+CCCC(14%)+CCCH(15%)
HCCC(25%)+OCCH(12%)+CCCC(11%)
792
789

821
846
CCH(11%)+CCCH(16%)+CCOH(40%)
873
873
CCH(16%)+CCCH(18%)+HCCH(14%)+CCCC(10%)
904
900

CC(16%)+CCH(20%)+CCC(10%)+HCCH(15%)+CCCH(13%)
CCCC(14%)+CCCH(17%)+HCCC(26%)+HCCH(18%)
946
926

968
968


CC(10%)+HCC(22%)+CCH(20%)+HCCH(22%)+CCCH(13%)
CN(10%)+NN(13%)+HCC(15%)+HCCH(18%)
987
984
1012
1022
1120
1176
1188
1211
1222
1267
1290
1334
1361
1377
1390
1413
1461
1469
1013
1026
1111
1170
1188
1211
1221
1277
1291
1333
1365
1378
1393
1416
1463
1467
HCC(20%)+HCCH(26%)

CC(22%)+HCC(19%)+HCCH(16%)





CCH(21%)+HCCH(23%)
CCH(17%)+HCCH(17%)+NCCH(10%)
CCH(32%)+CCCH(13%)
CCH(17%)+CCCH(11%)+HCCH(16%)
HCC(18%)+HCO(12%)+HCCH(22%)+HCCC(12%)


CC(13%)+HCC(17%)+HCCH(15%)
6.392
3.527
0.213
10.31
1.020
19.91
2.109
0.262
CC(10%)+HCC(21%)+HCCH(18%)+HCCC(10%)
HCC(23%)+HCCH(22%)
CCH(33%)+CCCH(19%)+HCCH(22%)

CC(18%)+HCC(31%)+HCH(15%)
HCH(26%)+HCC(33%)
CC(12%)+HCC(18%)+HCCH(10%)


HCH(35%)+CCCH(25%)+OCCH(25%)
HCH(14%)+CCH(13%)+HCCH(31%)+CCCH(27%)

1498
1579
1614
1677
2867
2927
2956
1490
1590
1630
1649
2895
2932
2956
3142
17.79
12.10
40.68
66.13
5.730
3.006
0.253
83.67
119
122
123
124
126
134
138
150
HCH(15%)+HCC(12%)+HCCH(23%)+HCCC(10%)







CC(29%)+HCC(13%)+CCC(16%)+CCH(13%)
CC(26%)+CCC(17%)+CCH(19%)
CC(20%)+CO(14%)+CCC(21%)+CCH(14%)
CH(88%)
CH(69%)
CH(70%)
OH(78%)
*Experimental frequencies from IR spectrum in cm-1.
**Potential energy distribution calculated at B3LYP/6-311++G(d,p) level of theory. Only contributions more
than 10% are listed
Vibrational modes: ν: stretchin ; δ: bendin ; τ: torsion
Table 4 The vibrational spectral data of 4b
Exp.
557
Mode No.
39
Freq
561
IIR
PED (%)
CCC(14%)+CCH(10%)+CCCC(12%)+CCCH(18%)+HCCH(10%)
1.149
0.099
2.886
1.021
0.268
0.286
2.126
5.407
2.228
0.257
1.801
1.533
3.711
5.894
2.552
0.096
4.728
3.157
100

597
598
41





CCCC(24%)+CCCH(16%)+CCCO(11%)
628
628
42
HCCH(20%)+HCCC(11%)+OCCH(10%)
653
654
44
OCCC(20%)+CCCC(22%)+CCCH(28%)
683
682
46
CNNN(14%)+NNNN(10%)+NNCC(11%)+NNCH(21%)
HCCH(14%)+CSCN(12%)+NCNN(18%)+CNNN(11%)+NNCH(10%)
717
730
47
744
742
49
HCC(13%)+HCCH(22%)+CCCC(10%)
788
781
53

HCCC(39%)+OCCH(10%)+CCCC(15%)
HCCC(37%)+OCCH(10%)+
804
791
54

852
853
56
CCH(20%)+CCCH(25%)+HCCH(13%)
877
876
58
CCH(16%)+HCCC(18%)+HCCH(14%)+CCCC(10%)
894
896
60
CC(12%)+CCH(25%)+HCCH(21%)+CCCH(10%)
970
968
64










CCH(22%)+HCCH(22%)+HCCC(13%)
1049
1078
1116
1174
1222
1263
1334
1363
1388
1415
1430
1461
1496
1585
1620
1670
2854
2869
2925
2958
1045
1089
1114
1186
1221
1277
1329
1365
1385
1416
1428
1463
1490
1589
1631
1648
2894
2895
2939
2953
70
HCC(16%)+HCCH(26%)+HCCC(13%)+HCOC(10%)
HCC(16%)+NCH(10%)+CCH(14%)+HCCH(27%)+HCCC(13%)
CCH(19%)+HCCH(25%)+CCCH(13%)
73
76
79
CCH(30%)+CCCH(10%)
83
HCC(18%)+HCO(12%)+HCCH(22%)+HCCC(13%)
CCH(18%)+HCCH(18%)+HCCC(10%)
86
2.117
0.236
5.907
19.31
17.26
2.195
20.23
12.86
42.18
72.73
5.792
5.976
5.812
0.451
94
CCH(28%)+CCC(11%)+HCCH(14%)+CCCH(11%)
CCH(33%)+CCCH(19%)+HCCH(22%)
97
101
105
107
111
119
122
123
124
125
126
134
137
HCC(25%)+NNCH(12%)+HCCH(19%)


CC(13%)+HCC(20%)+HCCH(12%)+HCCC(10%)
CC(16%)+HCC(18%)+CCC(11%)+CCCH(10%)
HCH(35%)+CCCH(25%)+OCCH(25%)
HCH(16%)+HCC(12%)+HCCH(24%)+HCCC(10%)+







CC(29%)+OCC(11%)+CCC(15%)+CCH(13%)+
CC(26%)+CCC(17%)+CCH(19%)
CC(14%)+CO(21%)+CCC(20%)+CCH(14%)
CH(76%)
CH(87%)
CH(67%)
CH(73%)

3144
87.97
150
OH(78%)
*Experimental frequencies from IR spectrum in cm-1.
**Potential energy distribution calculated at B3LYP/6-311++G(d,p) level of theory. Only contributions more
than 10% are listed
Vibrational modes: ν: stretchin ; δ: bendin ; τ: torsion
Table 5 The experimental and calculated 13C and 1H NMR isotropic chemical shifts (with
respect to TMS, all values in ppm) of 4a and 4b.
4a
4b
Atoms
C24
C16
C11
C38
C14
C13
C18
C12
C1
DFT
Exp.
Atoms
C24
C38
C11
C16
C14
C13
C18
C12
C1
DFT
Exp.
209.4
169.0
168.7
163.2
135.3
124.0
118.0
104.0
65.85
51.40
37.89
30.37
27.79
27.48
26.74
26.22
15.28
11.17
12.86
7.72
6.33
4.32
3.73
4.21
3.89
4.05
3.58
2.74
2.63
2.76
2.77
1.92
202.9
163.3
162.5
162.0
130.1
118.2
114.2
102.6
65.9
54.8
29.3
28.8
26.2
24.3
22.6
21.9
14.2
10.8
12.73
7.58
209.2
174.5
169.1
169.0
135.5
123.9
117.9
104.2
66.24
57.99
35.45
31.15
28.44
28.02
27.06
26.32
15.22
11.25
12.79
7.68
6.41
4.58
4.18
4.41
3.92
3.98
3.37
2.74
2.63
2.77
2.76
1.92
202.9
163.3
162.3
162.1
130.1
118.3
114.4
102.5
65.9
48.9
29.6
29.0
26.2
24.4
22.4
22.0
14.2
10.9
12.75
7.60
C43
C7
C4
C43
C7
C4
C17
C29
C44
C21
C26
C47
H25
H19
H15
H46
H45
H2
H3
H8
H9
H22
H23
H34
H35
H36
H6
C44
C17
C29
C21
C26
C47
H25
H19
H15
H46
H45
H2
H3
H8
H9
H22
H23
H34
H35
H36
H5
6.43
6.44
4.51
4.18
3.40
2.64
4.18
4.18
3.55
2.65
2.56
2.29
2.57
2.51
2.42
2.35-2.45

H5
2.41
1.70
1.65
1.46
1.37
1.20
0.92
0.85
1.21
0.99
1.05
H6
2.36
2.04
1.68
1.48
1.38
1.23
0.95
0.96
1.18
0.98
1.02
H48
H49
H27
H28
H50
H51
H52
H31
H32
H33
H48
H49
H27
H28
H50
H51
H52
H31
H32
H33
2.02
1.54
1.92
1.52-1.62
0.90-1.00
0.90-1.00
Table 6. Minimum Inhibitory Concentrations (MIC, µg/mL) of 4a and 4b
MIC values (µg/mL)
S. aureus S. epidermidis E. coli
Compounds
4a
4b
Gentamicin
Vancomycin
Imipenem
Fluconazole
P. aeruginosa
S. maltophilia
C. albicans A. fumigatus
64
8
2
2
-
32
8
4
2
-
32
4
4
-
8
-
32
16
8
-
16
-
32
16
4
-
4
32
16
-
16
16
-
-
-
-
-
-
-
-
32
32
Table 7 Minimum Bactericidal Concentrations (MBC, µg/mL) and Minimum Fungicidal
Concentrations (MFC, µg/mL) of 4a and 4b
MBC/MFC values (µg/mL)
Compounds
4a
4b
S. aureus
>128
32
S. epidermidis E. coli
P. aeruginosa
S. maltophilia
C. albicans
A. fumigatus
128
64
16
8
128
64
16
-
128
64
32
-
64
32
16
-
64
32
-
64
64
-
Gentamicin
4
Vancomycin 16
-
-
Imipenem
Fluconazole
-
-
-
-
32
-
32
-
8
-
-
-
64
128
Table S1 Optimized geometric parameters of 4a and 4b
4a
4b
4a
4b
4a
4b
Bond Lengths (Å)
Bond Lengths (Å)
Bond Angles ()
Bond Angles ()
Dihedral Angles ()
Dihedral Angles ()
C1-H2
1.095
1.095
1.519
1.434
1.096
1.093
C1-H2
C1-H3
C1-C4
C1-O10
C4-H5
C4-H6
1.095
1.095
1.519
1.435
1.096
1.093
H2-C1-H3
108.7
110.9
109.7
110.0
109.7
107.9
H2-C1-H3
108.8
110.8
109.7
110.2
109.6
107.8
H2-C1-C4-H5
179.69
-64.24
59.35
H2-C1-C4-H5
178.00
-66.10
57.21
C1-H3
C1-C4
C1-O10
C4-H5
C4-H6
H2-C1-C4
H2-C1-O10
H3-C1-C4
H3-C1-O10
C4-C1-O10
H2-C1-C4
H2-C1-O10
H3-C1-C4
H3-C1-O10
C4-C1-O10
H2-C1-C4-H6
H2-C1-C4-C7
H3-C1-C4-H5
H3-C1-C4-H6
H3-C1-C4-C7
H2-C1-C4-H6
H2-C1-C4-C7
H3-C1-C4-H5
H3-C1-C4-H6
H3-C1-C4-C7
-60.11
55.97
-61.60
54.30
179.55
177.61

C4-C7
1.529
1.089
1.091
1.846
1.361
1.408
1.402
1.381
1.080
1.403
1.510
1.405
1.083
1.426
1.342
1.542
1.093
1.093
1.465
0.991
1.531
1.095
1.095
1.515
1.239
1.094
1.095
1.095
1.093
1.093
1.089
1.754
1.322
1.352
1.360
1.359
1.461
1.285
1.532
1.093
1.091
1.531
1.095
1.094
1.092
1.094
C4-C7
C7-H8
C7-H9
C7-S37
1.530
1.089
1.091
1.843
C1-C4-H5
108.8
109.0
115.0
106.8
107.3
109.7
110.8
111.2
115.5
108.9
106.9
103.1
119.9
122.8
115.7
121.6
119.2
121.1
119.7
118.0
121.7
120.2
121.8
118.6
119.6
121.6
117.4
121.0
113.3
108.7
109.2
108.9
109.1
107.5
117.8
122.1
120.1
106.8
112.5
108.9
109.1
109.7
109.8
106.7
120.2
121.2
C1-C4-H5
108.8
108.8
114.8
106.8
107.8
109.7
110.7
110.8
115.4
108.5
107.6
103.4
119.9
122.8
115.7
121.5
119.3
121.0
119.7
118.1
121.7
120.3
121.8
118.6
119.6
121.6
117.4
121.0
113.3
108.7
109.2
108.9
109.1
107.5
117.8
122.1
120.1
106.8
112.5
108.9
109.1
109.7
109.8
106.7
120.2
121.2
O10-C1-C4-H5
O10-C1-C4-H6
O10-C1-C4-C7
59.57
O10-C1-C4-H5
O10-C1-C4-H6
O10-C1-C4-C7
H2-C1-O10-C11
H3-C1-O10-C11
C4-C1-O10-C11
C1-C4-C7-H8
C1-C4-C7-H9
C1-C4-C7-S37
H5-C4-C7-H8
H5-C4-C7-H9
H5-C4-C7-S37
H6-C4-C7-H8
H6-C4-C7-H9
H6-C4-C7-S37
C4-C7-S37-C38
H8-C7-S37-C38
H9-C7-S37-C38
C1-O10-C11-C12
57.92
C7-H8
C1-C4-H6
C1-C4-H6
175.65
-60.77
58.51
173.82
-62.87
58.37
C7-H9
C1-C4-C7
C1-C4-C7
C7-S37
H5-C4-H6
H5-C4-H6
H2-C1-O10-C11
H3-C1-O10-C11
C4-C1-O10-C11
C1-C4-C7-H8
O10-C11
C11-C12
C11-C13
C12-C14
C12-H15
C13-C16
C13-C17
C14-C18
C14-H19
C16-C18
C16-O20
C17-C21
C17-H22
C17-H23
C18-C24
O20-H25
C21-C26
C21-H27
C21-H28
C24-C29
C24-O30
C26-H31
C26-H32
C26-H33
C29-H34
C29-H35
C29-H36
S37-C38
C38-N39
C38-N40
N39-N41
N40-N42
N40-C43
N41-N42
C43-C44
C43-H45
C43-H46
C44-C47
C44-H48
C44-H49
C47-H50
C47-H51
O10-C11 1.360
H5-C4-C7
H5-C4-C7
-60.77
179.41
175.87
54.64
-61.00
179.11
174.25
53.87
C11-C12
C11-C13
C12-C14
1.408
1.402
1.381
H6-C4-C7
H6-C4-C7
C4-C7-H8
C4-C7-H8
C4-C7-H9
C4-C7-H9
C1-C4-C7-H9
C12-H15 1.080
C4-C7-S37
C4-C7-S37
C1-C4-C7-S37
-62.38
54.69
-63.25
52.93
C13-C16
C13-C17
C14-C18
1.403
1.510
1.405
H8-C7-H9
H8-C7-H9
H5-C4-C7-H8
H8-C7-S37
H8-C7-S37
H5-C4-C7-H9
-66.54
176.44
-60.90
177.87
60.85
-67.45
175.43
-62.96
176.66
59.54
H9-C7-S37
H9-C7-S37
H5-C4-C7-S37
C14-H19 1.083
C16-C18 1.426
C16-O20 1.343
C17-C21 1.542
C1-O10-C11
O10-C11-C12
O10-C11-C13
C12-C11-C13
C11-C12-C14
C11-C12-H15
C14-C12-H15
C11-C13-C16
C11-C13-C17
C16-C13-C17
C12-C14-C18
C12-C14-H19
C18-C14-H19
C13-C16-C18
C13-C16-O20
C18-C16-O20
C13-C17-C21
C13-C17-H22
C13-C17-H23
C21-C17-H22
C21-C17-H23
H22-C17-H23
C14-C18-C16
C14-C18-C24
C16-C18-C24
C16-O20-H25
C17-C21-C26
C17-C21-H27
C17-C21-H28
C26-C21-H27
C26-C21-H28
H27-C21-H28
C18-C24-C29
C18-C24-O30
C1-O10-C11
O10-C11-C12
O10-C11-C13
C12-C11-C13
C11-C12-C14
C11-C12-H15
C14-C12-H15
C11-C13-C16
C11-C13-C17
C16-C13-C17
C12-C14-C18
C12-C14-H19
C18-C14-H19
C13-C16-C18
C13-C16-O20
C18-C16-O20
C13-C17-C21
C13-C17-H22
C13-C17-H23
C21-C17-H22
C21-C17-H23
H22-C17-H23
C14-C18-C16
C14-C18-C24
C16-C18-C24
C16-O20-H25
C17-C21-C26
C17-C21-H27
C17-C21-H28
C26-C21-H27
C26-C21-H28
H27-C21-H28
C18-C24-C29
C18-C24-O30
H6-C4-C7-H8
H6-C4-C7-H9
H6-C4-C7-S37
C4-C7-S37-C38
H8-C7-S37-C38
H9-C7-S37-C38
C1-O10-C11-C12
C1-O10-C11-C13
O10-C11-C12-C14
O10-C11-C12-H15
C13-C11-C12-C14
C13-C11-C12-H15
O10-C11-C13-C16
O10-C11-C13-C17
C12-C11-C13-C16
C12-C11-C13-C17
C11-C12-C14-C18
C11-C12-C14-H19
H15-C12-C14-C18
H15-C12-C14-H19
C11-C13-C16-C18
C11-C13-C16-O20
C17-C13-C16-C18
C17-C13-C16-O20
C11-C13-C17-C21
C11-C13-C17-H22
C11-C13-C17-H23
C16-C13-C17-C21
C16-C13-C17-H22
C16-C13-C17-H23
C12-C14-C18-C16
C12-C14-C18-C24
H19-C14-C18-C16
H19-C14-C18-C24
-74.83
48.97
-76.40
47.73
C17-H22 1.093
C17-H23 1.093
163.71
0.46
162.38
-0.10
C18-C24
O20-H25 0.991
C21-C26 1.531
1.464
-179.56 C1-O10-C11-C13
179.90
179.75
-0.23
179.71
-0.06
O10-C11-C12-C14
O10-C11-C12-H15
C13-C11-C12-C14
C13-C11-C12-H15
C21-H27 1.095
C21-H28 1.095
-0.27
-0.25
C24-C29
1.515
179.96
179.77
-179.45
-0.59
C24-O30 1.239
C26-H31 1.094
C26-H32 1.095
C26-H33 1.095
C29-H34 1.093
C29-H35 1.093
C29-H36 1.089
-179.47 O10-C11-C13-C16
-0.65
0.50
O10-C11-C13-C17
C12-C11-C13-C16
C12-C11-C13-C17
C11-C12-C14-C18
0.55
179.33
0.03
179.41
-0.03
-179.85 C11-C12-C14-H19
-179.96
179.95
0.02
179.80
-0.07
H15-C12-C14-C18
H15-C12-C14-H19
C11-C13-C16-C18
C11-C13-C16-O20
S37-C38
1.759
C38-N39 1.357
C38-N40 1.332
N39-N41 1.314
N40-N42 1.333
N41-N42 1.320
N42-C43 1.462
-0.52
-0.58
179.52
179.45
-179.46
0.57
-179.36 C17-C13-C16-C18
0.68
C17-C13-C16-O20
C11-C13-C17-C21
C11-C13-C17-H22
C11-C13-C17-H23
C16-C13-C17-C21
C16-C13-C17-H22
-89.65
149.16
32.13
89.14
-32.05
-89.50
149.30
32.27
C43-C44
1.531
C43-H45 1.092
C43-H46 1.091
89.34
-31.86
-148.89
0.00
C44-C47
1.531
-149.07 C16-C13-C17-H23
-0.04 C12-C14-C18-C16
-179.97 C12-C14-C18-C24
C44-H48 1.093
C44-H49 1.094
C47-H50 1.092
C47-H51 1.094
-179.98
179.93
-0.05
179.83
-0.09
H19-C14-C18-C16
H19-C14-C18-C24

C47-H52
1.094
C47-H52 1.094
C29-C24-O30
C21-C26-H31
C21-C26-H32
C21-C26-H33
H31-C26-H32
H31-C26-H33
H32-C26-H33
C24-C29-H34
C24-C29-H35
C24-C29-H36
H34-C29-H35
H34-C29-H36
H35-C29-H36
C7-S37-C38
118.6
111.3
111.3
111.1
107.6
107.7
107.6
111.1
111.1
108.4
107.7
109.3
109.3
100.1
127.6
123.7
108.6
105.7
107.5
131.1
121.4
111.3
106.8
112.9
107.5
106.2
111.1
111.0
107.9
111.7
109.2
108.5
110.1
110.3
107.0
110.7
111.4
111.5
107.6
107.6
107.8
C29-C24-O30
C21-C26-H31
C21-C26-H32
C21-C26-H33
H31-C26-H32
H31-C26-H33
H32-C26-H33
C24-C29-H34
C24-C29-H35
C24-C29-H36
H34-C29-H35
H34-C29-H36
H35-C29-H36
C7-S37-C38
118.6
111.3
111.3
111.1
107.7
107.7
107.6
111.1
111.1
108.4
107.7
109.3
109.3
100.4
125.8
122.0
112.2
106.0
101.4
106.5
113.8
123.1
123.0
112.4
107.3
105.6
111.1
111.5
108.7
111.5
108.8
108.8
110.3
110.2
107.1
110.7
111.5
111.4
107.6
107.6
107.8
C13-C16-C18-C14
C13-C16-C18-C24
O20-C16-C18-C14
O20-C16-C18-C24
C13-C16-O20-H25
C18-C16-O20-H25
C13-C17-C21-C26
C13-C17-C21-H27
C13-C17-C21-H28
H22-C17-C21-C26
H22-C17-C21-H27
H22-C17-C21-H28
H23-C17-C21-C26
H23-C17-C21-H27
H23-C17-C21-H28
C14-C18-C24-C29
C14-C18-C24-O30
C16-C18-C24-C29
C16-C18-C24-O30
C17-C21-C26-H31
C17-C21-C26-H32
C17-C21-C26-H33
H27-C21-C26-H31
H27-C21-C26-H32
H27-C21-C26-H33
H28-C21-C26-H31
H28-C21-C26-H32
H28-C21-C26-H33
C18-C24-C29-H34
C18-C24-C29-H35
C18-C24-C29-H36
O30-C24-C29-H34
O30-C24-C29-H35
O30-C24-C29-H36
C7-S37-C38-N39
C7-S37-C38-N40
S37-C38-N39-N41
N40-C38-N39-N41
S37-C38-N40-N42
S37-C38-N40-C43
N39-C38-N40-N42
N39-C38-N40-C43
C38-N39-N41-N42
C38-N40-N42-N41
C43-N40-N42-N41
C38-N40-C43-C44
0.30
C13-C16-C18-C14
0.32
-179.78 C13-C16-C18-C24
-179.74 O20-C16-C18-C14
-179.71
-179.71
0.26
0.18
O20-C16-C18-C24
C13-C16-O20-H25
C18-C16-O20-H25
179.54
-0.42
179.52
-0.45
-179.71 C13-C17-C21-C26
-179.77
-57.94
58.15
-57.89
58.18
-58.61
63.21
179.28
58.40
C13-C17-C21-H27
C13-C17-C21-H28
H22-C17-C21-C26
H22-C17-C21-H27
H22-C17-C21-H28
H23-C17-C21-C26
-58.67
63.16
179.25
58.37
-179.78 H23-C17-C21-H27
-179.80
-63.71
-0.10
S37-C38-N39
S37-C38-N40
N39-C38-N40
C38-N39-N41
C38-N40-N42
C38-N40-C43
N42-N40-C43
N39-N41-N42
N40-N42-N41
N40-C43-C44
N40-C43-H45
N40-C43-H46
C44-C43-H45
C44-C43-H46
H45-C43-H46
C43-C44-C47
C43-C44-H48
C43-C44-H49
C47-C44-H48
C47-C44-H49
H48-C44-H49
C44-C47-H50
C44-C47-H51
C44-C47-H52
H50-C47-H51
H50-C47-H52
H51-C47-H52
S37-C38-N39
S37-C38-N40
N39-C38-N40
C38-N39-N41
C38-N40-N42
N39-N41-N42
N40-N42-N41
N40-N42-C43
N41-N42-C43
N42-C43-C44
N42-C43-H45
N42-C43-H46
C44-C43-H45
C44-C43-H46
H45-C43-H46
C43-C44-C47
C43-C44-H48
C43-C44-H49
C47-C44-H48
C47-C44-H49
H48-C44-H49
C44-C47-H50
C44-C47-H51
C44-C47-H52
H50-C47-H51
H50-C47-H52
H51-C47-H52
-63.71
0.00
H23-C17-C21-H28
C14-C18-C24-C29
-179.98 C14-C18-C24-O30
-179.92 C16-C18-C24-C29
179.92
179.92
-0.05
0.10
C16-C18-C24-O30
C17-C21-C26-H31
C17-C21-C26-H32
C17-C21-C26-H33
H27-C21-C26-H31
H27-C21-C26-H32
H27-C21-C26-H33
H28-C21-C26-H31
H28-C21-C26-H32
179.91
-60.01
59.92
58.58
178.65
-61.42
-58.38
61.69
179.90
-60.01
59.90
58.55
178.64
-61.45
-58.42
61.67
-178.37 H28-C21-C26-H33
-178.42
-59.76
60.06
-59.82
59.98
C18-C24-C29-H34
C18-C24-C29-H35
-179.93 C18-C24-C29-H36
120.16 O30-C24-C29-H34
-120.03 O30-C24-C29-H35
-179.86
120.22
-119.97
0.11
0.06
O30-C24-C29-H36
C7-S37-C38-N39
C7-S37-C38-N40
-2.19
177.65
-1.68
179.05
-179.19
0.15
-179.81 S37-C38-N39-N41
0.34
N40-C38-N39-N41
S37-C38-N40-N42
N39-C38-N40-N42
C38-N39-N41-N42
179.60
2.90
179.28
-0.09
-0.53
-0.14
-177.24 C38-N40-N42-N41
-0.01
-0.01
0.52
C38-N40-N42-C43
N39-N41-N42-N40
N39-N41-N42-C43
N40-N42-C43-C44
-177.99
0.10
177.61
86.65
178.09
70.48

C38-N40-C43-H45
C38-N40-C43-H46
N42-N40-C43-C44
N42-N40-C43-H45
N42-N40-C43-H46
N39-N41-N42-N40
N40-C43-C44-C47
N40-C43-C44-H48
N40-C43-C44-H49
H45-C43-C44-C47
H45-C43-C44-H48
H45-C43-C44-H49
H46-C43-C44-C47
H46-C43-C44-H48
H46-C43-C44-H49
C43-C44-C47-H50
C43-C44-C47-H51
C43-C44-C47-H52
H48-C44-C47-H50
H48-C44-C47-H51
H48-C44-C47-H52
H49-C44-C47-H50
H49-C44-C47-H51
H49-C44-C47-H52
-36.25
N40-N42-C43-H45
-51.90
-167.74
-107.33
130.29
14.45
-151.54 N40-N42-C43-H46
-89.67
147.43
32.14
-0.32
N41-N42-C43-C44
N41-N42-C43-H45
N41-N42-C43-H46
N42-C43-C44-C47
N42-C43-C44-H48
N42-C43-C44-H49
H45-C43-C44-C47
H45-C43-C44-H48
H45-C43-C44-H49
H46-C43-C44-C47
H46-C43-C44-H48
-179.78
-57.89
58.44
179.30
-58.73
57.51
-59.81
62.15
178.40
60.22
-59.58
62.31
178.64
61.88
-176.23
-59.90
180.00
-60.22
60.32
-177.82 H46-C43-C44-H49
-61.58 C43-C44-C47-H50
-179.77 C43-C44-C47-H51
-60.05
60.46
C43-C44-C47-H52
H48-C44-C47-H50
H48-C44-C47-H51
H48-C44-C47-H52
H49-C44-C47-H50
H49-C44-C47-H51
H49-C44-C47-H52
58.97
58.78
178.75
-60.70
-59.07
60.71
178.50
-61.00
-59.03
60.70
-178.74
-178.80