A series of twelve 2-[(
The design of new compounds that focused on resistant bacteria, mycobacteria, and fungi has become one of the most important areas of antimicrobial research today, since resistance of pathogenic bacteria toward available antimicrobial drugs is rapidly becoming a major problem worldwide. The increasing incidences of tuberculosis (TB), the number of cases of multi-drug-resistant strains of
Benzoxazole and its isosteres benzimidazole and benzothiazole represent privileged structures, that is, they are useful ligands for more than one type of receptor or enzyme targets by judicious structural modifications. They are privileged structural units not only in the pharmaceutical industry but also in several other fields such as agricultural, electronic, and polymer chemistry. The benzoxazole system is present in numerous antimicrobial agents [
Benzoxazoles can be considered as structural bioisosteres of nucleotides such as adenine and guanine, which allow them to interact easily with the biopolymers of a living system [
Both pharmaceuticals and pesticides (including herbicides) are designed to target particular biological functions, and in many cases they target similar processes or have similar molecular sites of action. For many years, virtually all pharmaceutical companies had agrochemical divisions. Leads for pharmaceuticals and pesticides often overlap, in some cases leading to similar compounds used for human health and weed management purposes. Multiple activities of various herbicides/herbicide classes show potential pharmaceutical properties, both as therapeutic agents that act through human molecular target sites and those that act on infectious agents [
The prepared 2-styrylbenzoxazole-like compounds were designed as potential antimycobacterial agents and tested against three mycobacterial species. As it is known that a number of antimicrobial compounds display also photosynthesis inhibiting activity (bond to PS II) [
The chemicals were purchased from commercial sources (Sigma Aldrich, Acros Organics, TCI, Merck). Commercial grade reagents were used without further purification. Reactions were monitored by means of thin layer chromatography plates coated with 0.2 mm Silica Gel 60 F254 (Merck). TLC plates were visualized by UV irradiation (254 nm). The products were purified by crystallization, by means of column chromatography employing Silica Gel 60 (Merck). All melting points were determined on Melting Point B-540 apparatus (Buchi, Germany) and are uncorrected. NMR spectra were measured in CDCl3 solutions on a Bruker Avance 300 or 500 MHz apparatus. The chemical shifts
General procedure for synthesis of
A Waters Alliance 2695 XE HPLC separation module and a Waters Photodiode Array Detector 2996 (Waters Corp., Milford, MA, USA) were used. A Symmetry C18 5
Structure of 2-substituted benzoxazoles
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Comp. | R |
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|
MVa [cm−3] | [ | |||
MIC |
PET |
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MTB | MA | MK | ||||||
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0.9409 | 1.76 | 80.88 | 125 |
62.5 |
125 |
148.8 |
|
|
0.9325 | 1.42 | 103.61 | 125 |
62.5 |
125 |
76.3 |
|
|
0.9382 | 1.57 | 103.61 | 62.5 |
32 |
62.5 |
216.1 |
|
|
1.1225 | 2.24 | 111.37 | 62.5 |
62.5 |
62.5 |
199.3 |
|
|
1.1226 | 2.22 | 97.11 | 250 |
125 |
250 |
102.0 |
|
|
1.1271 | 2.33 | 92.25 | 250 |
250 |
500 |
516.6 |
|
|
1.1317 | 2.73 | 113.57 | 125 |
125 |
250 |
b |
|
|
0.9397 | 1.58 | 100.92 | 62.5 |
32 |
62.5 |
131.4 |
|
|
0.7503 | 0.95 | 62.74 | 62.5 |
62.5 |
125 |
224.1 |
|
|
1.0702 | 1.94 | 95.74 | 250 |
250 |
62.5 |
122.3 |
|
|
1.1411 | 2.61 | 99.65 | 125 |
250 |
500 |
777.5 |
|
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1.1394 | 2.56 | 123.65 | 125 |
125 |
125 |
351.0 |
|
— | — | — | 0.5 |
>250 |
>250 |
— | |
|
— | — | — | — | — | — | 1.9 |
acalculated for the uncharged molecules using ACD/Percepta (Advanced Chemistry Development, Inc., Toronto, ON, Canada, 2012); bprecipitation during experiment; MTB:
The
Chloroplasts were prepared from spinach (
The fluorescence emission spectra of aromatic amino acids (AAA) in spinach chloroplasts were recorded on fluorescence spectrophotometer F-2000 (Hitachi, Tokyo, Japan) using excitation wavelength
2-Methylbenzo[
Synthesis of 2-[(
Lipophilicity is a property that has a major effect on ADME/Tox properties as well as pharmacological activity, because drugs mostly cross biological membranes through passive transport, which strongly depends on their lipophilicity. Lipophilicity has been studied and applied as an important drug property for decades. This parameter was measured by means of RP-HPLC and expressed as logarithm of capacity factor
Comparison of experimentally found log
Compounds from the series of 2-[(
Based on the results it can be stated that heterocycles demonstrated lower lipophilicity (
The discussed benzoxazoles
Dependence of
Also the following SAR observations were made for this series of compounds. Substitution by the phenyl ring showed similar activity as substitution by the furanyl ring. Substitution of
As was mentioned above, drugs and agrochemicals as biologically active compounds can target similar sites of action. Thus herbicides can also have molecular sites of action in mammals/nonplant organisms, but targeting compounds to biological systems with similar physicochemical properties can lead to completely different biological responses in plants and animals. For example, fluconazole was firstly discovered as a potent pesticide, and subsequently it was confirmed as an antifungal drug [
The activity of the evaluated substituted benzoxazoles related to inhibition of photosynthetic electron transport (PET) in spinach (
Relationships between PET inhibition log(1/MIC (mol/L)) in spinach chloroplasts and molar volume (MV (cm3)) of individual substituents in 2-[(
Based on the obtained results (see Table
An experiment with 2,5-diphenylcarbazide (DPC), an artificial electron donor acting in Z/D intermediate on the donor side of PS II, was performed to specify the site of action of the tested compounds in the photosynthetic apparatus. Practically complete restoration of photochemical activity of chloroplasts (up to 93% of the control) that was previously suppressed by the tested compounds indicated that their site of action is situated on the donor side of PS II. In our previous studies we found that the site of inhibitory action of
The interaction of studied compounds with aromatic amino acids (AAA) occurring in photosynthetic proteins of spinach chloroplasts situated in PS II was monitored by the quenching of AAA fluorescence at 334 nm. The fluorescence emission spectra of AAA of untreated spinach chloroplasts and of compound
Emission fluorescence spectra of aromatic amino acids in suspension of spinach chloroplasts without and with
A series of twelve 2-[(
The authors declare no conflict of interests.
The authors wish to acknowledge The Ministry of Education, Youth and Sports of the Czech Republic (for the financial support of the Faculty of Chemistry and Chemical Technology, University of Pardubice), the Slovak Grant Agency VEGA, Grant No. 1/0612/11, Project APVV-0061-11, and Sanofi-Aventis Pharma Slovakia.