Synthesis and Antibacterial Activity of New Chiral Aminoalcohol and Benzimidazole Hybrids

Abstract

New chiral aminoalcohol‐benzimidazole hybrids have been synthesized from commercially available aminoalcohols
[S(+)‐Phenylglycinol, S(−)‐ Phenylalaninol and S(+)‐ Leuicinol] and 2‐(chloromethyl)‐N‐tosyl‐1‐H‐benzimidazole. The synthesized compound were characterized by IR, NMR, and LC‐MS analysis. The antibacterial properties of aminoalcohol‐benzimidazole hybrid molecules 4 a, 4 b, and 4 c were investigated against both gram (+ve) and gram (‐ve) bacterial pathogens by the well‐diffusion method using several standarts. The cell‐based biological experiment was consistent with in silico studies. Furthermore, in silico studies revealed that all synthesized compounds could be suggested as potential drugs for inhibition of both peptide deformylase for bacteria and sterol 14α‐demethylase for yeast.

Full text

zBiological Chemistry & Chemical Biology
Synthesis and Antibacterial Activity of New Chiral
Aminoalcohol and Benzimidazole Hybrids
İlknur Çiçek,[a] Dr.Turgay Tunç,[b] Hatice Ogutcu,[c] Suzan Abdurrahmanoglu,[d] Aslıhan Günel,[a]
and Nadir Demirel*[a]
New chiral aminoalcohol-benzimidazole hybrids have been
synthesized from commercially available aminoalcohols
[S(+)-Phenylglycinol, S()- Phenylalaninol and S(+)- Leuicinol]
and 2-(chloromethyl)-N-tosyl-1-H-benzimidazole. The synthe-
sized compound were characterized by IR, NMR, and LC-MS
analysis. The antibacterial properties of aminoalcohol-benzimi-
dazole hybrid molecules 4 a,4 b, and 4 c were investigated
against both gram (+ve) and gram (-ve) bacterial pathogens
by the well-diffusion method using several standarts. The cell-
based biological experiment was consistent with in silico
studies. Furthermore, in silico studies revealed that all synthe-
sized compounds could be suggested as potential drugs for
inhibition of both peptide deformylase for bacteria and sterol
14α-demethylase for yeast.
1. Introduction
Benzimidazole, first synthesized by Hobrecker in 1872, is an
important heterocyclic compound found in many natural
products.[1–5] In medicinal chemistry, benzimidazole derivatives
are one of the highest significant and powerful structures.[6–7]
Since benzimidazoles have considerable bioactivities, such as
anti-protozoal, anti-microbial, anti-inflammatory, analgesic,
antioxidant, anthelmintic, anti-hypertensive, and anticancer
activity, they have an essential role in drug discovery.[8–9]
Furthermore, compounds that bear benzimidazole ring also
show important activity against several viruses such as human
cytomegalo virus, HIV and influenza.[10–11] In recent years, some
benzimidazole derivatives have found to have considerable
antibacterial activity.[12–16] The chiral aspects of benzimidazoles
derivatives have not attracted much attention due to the
numerous articles on benzimidazoles in the category of
numerous therapeutic agents in the medical field. Especially
after the emergence of bifunctional benzimidazoles in recent
years, strong researches have started in the chiral applications
of benzimidazole derivatives. Benzimidazoles have acquired an
important role in chiral processes because of their rigid
structure, the capability to form hydrogen bonding, basic
characteristics, (pKa=5.4) high stability, nucleophilic properties,
easy assembly of a chiral unit and having pyrrole and pyridine
type nitrogen atoms fused to the benzene ring.[17–19] The
biological and pharmacological properties of a chemical are
influenced by the chiral nature of the compound. In biological
processes, asymmetric centres have considerable importance.
The response of an organism to these molecules depends
on how these molecules fit into biological receptors. The use of
chiral chemicals as drugs such as anti-fungal, insecticides, anti-
arrhythmic, antihistaminic and anti-cancer and anti-microbial
reduces undesirable toxic and ecological effects as well as
unnecessary excess drug use.[20–21]
A number of review articles have been published that
provide a comprehensive overview of the antimicrobial activity
of benzimidazole derivatives.[22–25]
Peptide deformylase’s (PDF), which are essential metal-
loenzymes for cell growth, co-translationally remove the formyl
group carried by the initiator methionine, which requires
protein synthesis in bacteria.[26] They have been considered as a
potential target for a new type of antibiotics for bacteria.[27–28]
Besides the many types of PDF inhibitors,[29] Actinonin was the
first one that synthesized for this aim.[30] Due to the lack of
structural stability, actinonin showed weak or moderate activity
against the bacteria. Johnson and coworkers have been
examined the enzyme inhibition of some potential PDF
inhibitors against community-acquired pneumonia experimen-
tally in their studies.[31] On the other hand, inhibition of sterol
14α-demethylase, which is an essential enzyme for biosynthesis
of sterols, is considered as the primary target for potential
antifungal drug candidates.[32] The role of this enzyme activity
presence of anti-fungal drugs has been extensively studied by
researchers both experimentally and theoretically.[33–34] In order
to examine the mechanism of antimicrobial effect of the novel
compounds (4 a,4 b, and 4 c), an in silico study was planned
[a] İ. Çiçek, Dr. Aslıhan Günel, Prof. Nadir Demirel
Department of Chemistry, Faculty of Arts and Sciences
Ahi Evran University, 40100, Kırşehir, Turkey
Homepage: https://akademik.ahievran.edu.tr/site/nadirdemirel
E-mail: demireln@ahievran.edu.tr
[b] Dr.Turgay Tunç
Department of Chemistry Engineering and Process, Faculty of Engineer-
ing, University of Ahi Evran, Kırsehir, 40100, Turkey
[c] Prof. Hatice Ogutcu
Department of Field Crops, Faculty of Agriculture, University Ahi Evran,
Kırsehir, 40100,Turkey
[d] Dr. Suzan Abdurrahmanoglu
Department of Chemistry, Faculty of Arts and Science, Marmara
University, Istanbul, 34722, Turkey
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/slct.202000355
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based on the binding interaction between the ligands (4 a,4 b,
and 4 c) and peptide deformylase in both gram () and gram
(+) bacteria and sterol 14 α-demethylase in Candida albicans.
2. Results and Discussion
2.1. Chemistry
The synthesis of chiral amino alcohols-benzimidazole hybrid
starts with the reaction of monochloro acetic acid and 1,2-
diaminobenzene in 4 N HCl and then N-tosylation of 2-
(chloromethyl)-1-H-benzimidazole 1with p-toluensulfonyl
chloride in pyridine gave 2-(Chloromethyl)-1-[(4-methylphenyl)
sulfonyl]-1H-benzimidazole 2. All spectroscopic and physical
data of synthesized compound 1and 2are consistent with the
literature.[35–36] (Scheme 1) The chiral amino alcohols-benzimida-
zole hybrid compounds were synthesized the reaction of
commercially available chiral amino alcohols with the 2-
(chloromethyl)-N-tosyl-1-H-benzimidazole 2. (Scheme 1) The
nucleophilic substitution was performed in the presence of KI
in dry DMF using excess amino alcohols as a base. The
reactions resulted in high yield. (84–90%)
NMR spectra of the synthesized compounds appear as
expected. When the methylene protons are adjacent to an
asymmetric centre, the methylene protons are not equivalent
protons; as a result, they gave an AB system in the NMR
spectrum. The NMR spectra revealed that the AB system was
observed clearly in the case of Ha and Hb protons of 4 a,4 b,
and 4 c. (S4–S10)4 a and 4 c have two methylene groups
adjacent to an asymmetric centre. (Scheme -2) But AB system
was not observed in the case of Hc and Hd protons of 4 a and
4 c. Hc and Hd protons of 4 a seems as equivalent protons; as a
result, they gave a doublet. (S4) In compound 4 c, the meth-
ylene protons (Hc and Hd) adjacent to the asymmetric centre
has also another adjacent proton (methine), so the expected
AB system became a more complicated one.(S10)The meth-
ylene proton of the benzimidazole unit gave two doublets. This
system was observed in a similar
structure.[37–38] All the other spectral data were consistent
with the structures.
3. Biological activity
3.1. Antibacterial activity
The summary of inhibition zones (mm) was given in Table 1. It
has been well known that S.aureus, a versatile pathogen, is
multifarious in nature and varies in intensity of infection,
affecting the skin, soft tissue, respiratory system, bone joints,
and endovascular tissues.[39] After the breakage of the epithe-
lium, this extracellular pathogen bacteremia may cause vital
diseases such as pneumonia, osteomyelitis, endocarditis, and
Scheme 1. The synthesis of chiral amino alcohols benzimidazole hybrids.
Scheme 2. The diastereotopic proton of methylene groups in chiral amino
alcohol-benzimidazole hybrids.
Table 1. Inhibition zone (mm) of the synthesized compounds 4 a,4 b and 4c towards different Gram (+ve), Gram (ve) and yeast.
Compds Gram (
+
) Gram () Yeast
Micro-
coccus
luteus
Staphylo-
coccus
epidermis
Staphylo-
coccus
aureus
Bacillus
cereus
Pseudo-
monas
putida
Klebsiella
pneumonia
Entero-
bacter
aerogenes
Salmonella
typhi H
Escherichia
coli
Proteus-
vulgaris
Candida
albicans
4 a 20 23 21 17 19 20 18 17 20 20 19
4 b 21 20 24 16 20 15 15 16 20 16 20
4 c 20 22 26 20 23 22 20 20 22 21 20
AMP 10a22 26 30 23 8 21 21 11 10 17 NT
SXT 25a21 25 24 25 18 20 19 17 18 19 NT
AMC 30a25 27 30 20 15 21 20 19 14 20 NT
K 30a23 25 25 28 14 23 24 20 25 21 NT
NYS 100aNT NT NT NT NT NT NT NT NT NT 20
[a] SXT25, sulfamethoxazole 25 μg; AMP10, Ampicillin 10 μg; NYS100, Nystatin 100 μg; K30, Kanamycin 30 μg; AMC30, Amoxycillin 30 μg; NT: not tested;
Diameter of zone inhibition (mm).
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septic shock.[40] Although compound 4 b exhibited the same
level of activity as STX25 (24 mm) against S. aureus, compound
4 c (26 mm) showed higher inhibition effect than standard
antibiotics SXT25 (24 mm) and K30 (25 mm) against S.aureus.
(Table 1, S13) Furthermore, compound 4 c showed good
inhibition activity as a standard antibiotic AMC30 (20 mm)
against well-known an opportunist pathogen B. cereus that is
associated with food-borne illness.[41] In recent years, P. putida
has become a significant human pathogen. P. putida creates
nosocomial infections, especially in immunocompromised
patients and in patients with medical devices or catheters,
because they may colonize moist and lifeless hospital
surfaces.[42–43] All compounds 4 a, (19 mm) 4 b (20 mm), and 4 c
(23 mm) showed higher inhibition activity against P. putida
than all standard antibiotics tested. (Table 1, S13) In the case of
K. pneumonia,4 c (22 mm) showed better activity than the
standard antibiotics except for K30. (Table 1, S13) In addition,
4 c showed the same activity as K30 (20 mm) against E.
enterogenes. (Table 1, S13)Salmonella serovars cause various
clinical symptoms, from asymptomatic infection to acute
typhoid-like syndromes in infants or certain highly susceptible
animals.[44] Compounds 4 a and 4 c showed the same level of
inhibition activity as standard antibiotics STX25 (17 mm) and
K30 (20 mm) respectively against this important pathogen
Salmonella typhi H (Table 1, S13) In the case of E. coli,4 a
(20 mm), 4 b (20 mm) and 4 c (22 mm) showed better activity
than the standard antibiotics except for K30. (Table 1, S13)P.
vulgaris is another crucial pathogen. Compounds 4 a and 4 c
showed the same inhibition activity as standard antibiotics
AMC30 (20 mm) and K30 (21 mm) against P. vulgaris. (Table 1,
S13) Compound 4 b was found to have the same degree of
inhibition activity as a standard antibiotic SXT 25 having a
21 mm zone against M. luteus. (Table 1, S13) Systemic fungal
infections are vital for the immune compromised patient (organ
or bond transplantation, aids, cancer chemotherapy). Candida
albicans have revealed as significant causes of mortality and
morbidity in this type of patient. 4 a, and 4 c showed similar
inhibition activity as a standard antifungal against C. albicans.
(Table 1, S13) In general, compound 4 c was found to be a
higher level of inhibition activity than 4 a and 4 b in the case of
gram () bacteria. The result also clearly showed that all
compounds have approximately the same level of inhibition
activity against gram (+) bacteria and yeast. Benzimidazole
units are common in all three compounds, and the structural
difference is due to the amino alcohol moiety.
3.2. Molecular Docking
Results of the computational studies were evaluated by means
of binding energies of all the novel compounds with the PDF
of E. coli, S. aureus, and sterol 14α-demethylase of C. albicans.
The binding affinities of 4 a,4 b, and 4 c, which observed as a
negative score with unit expressed kcal/mol, were presented in
Table 2. As seen in Table 2, all the compounds were success-
fully docked with the targeted proteins. Average binding
energies for all compounds were calculated as 8.0 0.5 kcal/
mol except the one between 4 b and C. albicans (5TZ1) as
9.4 kcal/mol, which is the highest score.
In Fıgure 2, docking pose and binding interaction between
ligand 4 a and S.auerus (1LM4) were presented. In this case, the
ligand has formed hydrogen bonds (length less than 3 Å) with
the active residues Asp87, Met89 besides the hydrophobic
interaction with Ile140 (alkyl), Met189 (pi-sigma), Try88 (pi-alkyl)
residues and also van der Waals interaction with Asp134
residue.
For the discussion of antimicrobial properties of synthesized
compounds, the binding pose and interaction with the sterol
14α-demethylase in C. albicans were also examined. As seen in
Figure 3, all intermolecular interactions could be evidence of
the inhibition effect of ligand 4 b, which showed the highest
binding energy.[32] For instance, there are hydrogen bonds
(bond length <3 Å) formed between His377 and Ser378,
between Phe380 and Try118, between His377 and ligand, etc.,
Hydrophobic interactions were also determined between Ala61
and Leu87 (alkyl), between Leu88 and ligand (pi-sigma), etc., All
these interactions are inconsistent with obtained by using
other antifungal drugs such as posaconazole.[32]
Table 2. Binding affinities of compounds (kcal/mol).
Compounds E. coli (1LRU) S. aureus (1LM4) C. albicans (5TZ1)
4 a 8.3 8.3 8.4
4 b 8.0 8.2 9.4
4 c 7.6 8.1 8.4
Ligand 4 a has formed hydrogen bonds with the active sites such as Arg97,
Gly89, Ile44, Val62 of 1LRU (E.coli) with bond length <3 Å as seen in
Figure 1. Besides, there are hydrophobic (pi-alkyl) interaction between
ligand and Leu91, Cys129 residues, and also van der Waals interaction with
Arg97 and Glu88. It was observed that the other two ligands showed
similar interactions.
Figure 1. Interaction between compound 4 a and peptide deformylase (PDB:
1LRU) of E. coli (Discovery studio image).
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The results of ADME (absorption, distribution, metabolism,
and excretion) predictions of all compounds by SwissADME
were given in Table 3. Lipinski’s rules state that oral bio-
availability of a drug is likely to exist if it possesses the
following features: MW500; H-bond donors5; H-bond
acceptors10; c logP values5. The results of all three
compounds showed that they all obeyed the Lipinski’s rules.
(Table 3) The ADME results also showed that with high gastro-
intestinal absorption, no brain-blood barrier (BBB) permeation,
and even negative lop Kpvalue, which refers to less skin
permeation, all of them could be recognized as a drug like
potential.
4. Conclusion
In conclusion, new chiral amino alcohol-benzimidazole hybrids
4 a,4 b, and 4 c were synthesized and antibacterial properties
were investigated against both Gram (+ve) and Gram (-ve)
bacterial pathogens. All three chiral molecules showed good
activity against tested pathogens. Molecular docking studies
for the 4 a,4 b, and 4 c indicated that all compounds interacted
with the the PDF of E. coli,S. aureus, and sterol 14α-demeth-
ylase of C. albicans with high binding energies. The highest
binding energy was observed between 4 b and C. albicans
(5TZ1) as 9.4 kcal/mol. Furtheremore all three new chiral
molecules interacted with the target protein PDF of E. coli,S.
aureus, and sterol 14α-demethylase of C. albicans through H-
bond, hydrophobic and van der Waals interaction with high
binding energies.
The ADME (absorption, distribution, metabolism, and ex-
cretion) studies indicated that all three new chiral molecules
4 a,4 b, and 4 c have high gastrointestinal absorption, no brain-
blood barrier (BBB) permeation, and less skin permeation. In
briefly, new chiral aminoalcohol-benzimidazole hybrid mole-
cules could be recognized as a drug like potential towards PDF
of E. coli,S. aureus, and sterol 14α-demethylase of C. albicans.
Supporting Information Summary
Experimental Section, General Method, Test Microorganisms,
Molecular Docking, Detection of Antimicrobial Activity and
Preparation and Analytical Data of 4 a,4 b, and 4 c can be found
in the Supporting Information.
Acknowledgments
The financial support of this work by the Ahi Evran University
grant FEF.A4.19.006 is gratefully acknowledged
Conflict of Interest
The authors declare no conflict of interest.
Figure 2. Interaction between compound 4 a and peptide deformylase
(PDB:1LM4) of S.auerus (Discovery studio image).
Figure 3. Interaction between compound 4 a and sterol 14α-demethylase
(PDB:5TZ1) of Candida albicans (Discovery studio image).
Table 3. The results of ADME analysis of compounds.
Sample MW/
gmol1
HBD
(5)
HBA
(10)
cLogP
(5)
Molar
refractivity
Log Kp
(cm/s)
4 a 435.54 2 5 3,56 121.61 6.28
4 b 421.51 2 5 3,33 116.80 6.54
4 c 401.52 2 5 3,41 11.54 6.26
MW: Molecular weight <500, HBD: Hydrogen bond donor 5, HBA:
Hydrogen bond acceptor 10, cLogP: High lipophilicity (expressed as
consensus LogP) <5, Molar refractivity should be between 40 and 130, Log
Kp: skin permeability: The more negative log Kp, the less skin permeant is
the compound
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Keywords: Benzimidazole ·Antibacterial Agent ·
Aminoalcohol ·PDF inhibitor ·Molecular docking
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Submitted: January 27, 2020
Accepted: April 6, 2020
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