Next Article in Journal
Investigation of the Effect of the Degree of Processing of Radix Rehmanniae Preparata (Shu Dihuang) on Shu Dihuangtan Carbonization Preparation Technology
Next Article in Special Issue
Ionic Liquid-Catalyzed Green Protocol for Multi-Component Synthesis of Dihydropyrano[2,3-c]pyrazoles as Potential Anticancer Scaffolds
Previous Article in Journal
Application of An Improved HPLC-FL Method to Screen Serine Palmitoyl Transferase Inhibitors
Previous Article in Special Issue
Facile Synthesis of Novel Coumarin Derivatives, Antimicrobial Analysis, Enzyme Assay, Docking Study, ADMET Prediction and Toxicity Study
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 22
Issue 7
10.3390/molecules22071199
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Photosynthesis-Inhibiting Activity of 1-[(2-Chlorophenyl)carbamoyl]- and 1-[(2-Nitrophenyl)carbamoyl]naphthalen-2-yl Alkylcarbamates †

by
Tomas Gonec
1,*,
Josef Stranik
1,
Matus Pesko
2,
Jiri Kos
3,
Michal Oravec
4,
Katarina Kralova
5 and
Josef Jampilek
3,*
1
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 61242 Brno, Czech Republic
2
Department of Environmental Ecology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 84215 Bratislava, Slovakia
3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia
4
Global Change Research Institute CAS, Belidla 986/4a, 60300 Brno, Czech Republic
5
Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 84215 Bratislava, Slovakia
*
Authors to whom correspondence should be addressed.
†
Preliminary results were presented at The 19th Electronic Conference on Synthetic Organic Chemistry (ECSOC-19, http://sciforum.net/conference/80/paper/3079), 1–30 November 2015 (paper b006) and The 20th Electronic Conference on Synthetic Organic Chemistry (ECSOC-20, http://sciforum.net/conference/94/ paper/3535), 1–30 November 2016 (paper b004).
Molecules 2017, 22(7), 1199; https://doi.org/10.3390/molecules22071199
Submission received: 16 June 2017 / Revised: 11 July 2017 / Accepted: 14 July 2017 / Published: 17 July 2017
(This article belongs to the Special Issue ECSOC-20)
Browse Figures
Versions Notes

Abstract

:
Eight 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates and eight 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The PET-inhibiting activity of the compounds was relatively low; the corresponding IC50 values ranged from 0.05 to 0.664 mmol/L; and the highest activity within the series of compounds was observed for 1-[(2-chlorophenyl)-carbamoyl]naphthalen-2-yl propylcarbamate. It has been proven that the compounds are PET-inhibitors in photosystem II. Despite rather low PET-inhibiting activities, primary structure-activity trends can be discussed.

1. Introduction

Although naphthalene can be considered as the simplest compound from the group of arenes, it is one of the most interesting arenes. Naphthalene-based drugs include not only clinically used anti-infective chemotherapeutics—e.g., naftifine, terbinafine, tolnaftate, nafcillin—but also other compounds with significant antimicrobial effects, e.g., dye naftol [1,2,3]. The naphthalene scaffold can be found in many other bioactive compounds [1,3,4,5,6,7,8]; therefore, this scaffold can be considered a privileged structure [9,10,11,12].
Our research group prepared and tested naphthalenecarboxamides and various positional isomers of hydroxynaphthalenecarboxamides as potential antimicrobial and antiprotozoal compounds [13,14,15,16,17,18,19,20,21,22]. The presence of an amide (–CONH–) and/or a carbamate (–OCONH–) group(s) in the structure of compounds enables interactions with various enzymes or enzymatic systems ([23,24,25,26] and references therein). In addition, these moieties can be found in many herbicides acting as photosynthesis inhibitors, e.g., [27,28,29,30,31,32,33,34,35]. Though currently about 20 mechanisms of action of herbicides are known [36], over 50% of marketed herbicides act by reversible binding to photosystem II (PS II) [37], resulting in interruption of the photosynthetic electron transport (PET) [38,39,40]. Various types of substituents modify properties of amide and carbamate moieties [41,42].
In the middle of the 1970s, it was found that salicylanilides belong to effective uncoupling agents of oxidative phosphorylation [43,44,45], and acceleration of the deactivation reactions of water splitting enzyme system Y by 3-tert-butyl-5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide was observed [44]. Substituted salicylanilides or their bioisosteres inhibited PET in spinach chloroplasts [13,14,15,16,17,18,31,32,33,34,35] and reduced chlorophyll content in green alga, Chlorella vulgaris [31,35,46,47]. It is important to note that in addition to the above-mentioned herbicidal activity, the wide spectrum of biological effects of salicylanilides includes, for example, antibacterial, antimycobacterial, antifungal, and anthelmintic activity; however, their mechanism of action is still under investigation ([25,26] and references therein).
In the context of the above-mentioned facts, 1-[(2-chlorophenyl)-carbamoyl]naphthalen-2-yl alkylcarbamates and 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates were prepared [22] and tested for their photosynthesis-inhibiting activity—the PET inhibition in spinach chloroplasts (Spinacia oleracea L.). The structure–activity relationships are discussed.

2. Results and Discussion

2.1. Chemistry

A microwave-assisted synthesis [15] gave N-(2-chlorophenyl)-2-hydroxynaphthalene-1-carboxamide (1) and N-(2-nitrophenyl)-2-hydroxynaphthalene-1-carboxamide (2). Then these pattern compounds 1 and 2 with triethylamine and appropriate alkyl isocyanates yielded a series of eight 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl carbamates 1a–1h and eight 1-[(2-nitrophenyl)-carbamoyl]naphthalen-2-yl carbamates 2a–2h, see Scheme 1 [22].

2.2. Inhibition of Photosynthetic Electron Transport (PET) in Spinach Chloroplasts

The PET-inhibiting activity was expressed by IC50 value (compound concentration in mol/L causing 50% inhibition of PET), see Table 1. Both pattern anilides 1 and 2 showed higher PET-inhibiting activity than their carbamate counterparts. The highest activity within the series of the chlorinated carbamates 1a–1h (series I) was observed for 1-[(2-chlorophenyl)carbamoyl]-naphthalen-2-yl propylcarbamate (1b, IC50 = 0.08 mM), while the highest PET-inhibiting activity within the series of the nitrated carbamates 2a–2h (series II) was observed for 1-[(2-nitrophenyl)-carbamoyl]naphthalen-2-yl pentylcarbamate (2e, IC50 = 0.233 mM), Table 1. Despite rather low PET-inhibiting activities, primary dependences between structure of the compounds and their PET inhibition can be discussed.
ACD/Percepta ver. 2012 was used for prediction of various physicochemical descriptors, from which only those that best characterize the influence of PET-inhibiting activity on compound structure are listed in Table 1. The lipophilicity of compounds 1a–1h, expressed as calculated log P (clogP) values, ranged from 3.94 (compound 1a, R = C2H5) to 7.19 (compound 1h, R = C8H17), while the clogP values of compounds 2a–2h ranged from 3.58 (compound 2a, R = C2H5) to 7.22 (compound 2h, R = C8H17). Lipophilicity increases with the lengthening of the alkyl tail. Propyl showed a higher clogP value than isopropyl. In general, it can be stated that lipophilicity of these compounds is rather high. Recommended log P value for drugs and agrochemicals is ≤5 [48]. The bulkiness of individual substituents R2 expressed as molar volume MV [cm−3] was calculated also for the hydrophobic N-alkyl tail; its values ranged from 47.29 to 146.33. This parameter represents the bulk of substituents (i.e., tail length/branching) of each compound relative to other members of the same series. Taft polar constants σ* representing electronic properties of individual alkyl substituents of the discussed compounds were also included in Table 1; they ranged from −0.25 to −0.11.
The dependence of the PET-inhibiting activity expressed as log(1/IC50 [mol/L]) of compounds 1, 1a–1h and 2, 2a–2h in spinach chloroplasts on lipophilicity expressed as clogP is shown in Figure 1A,B, while Figure 1C illustrates this dependence for all investigated compounds 1–2h.
Anilide 1 of series I was considerably more active than N-alkyl substituted compounds 1a–1h. While ethyl derivative 1a of series I was inactive due to low lipophilicity, propyl derivative 1c—showing sufficient lipophilicity together with suitable aqueous solubility—was the most active compound. With the elongation of the alkyl chain in the R substituent, the aqueous solubility of the evaluated derivatives decreased, and at higher concentrations they precipitated from the solution during the experiment. Among compounds of series I, the lowest solubility was shown by butyl derivative 1d, and the solubility of derivatives 1d–1h with longer alkyl chains was similar and significantly lower than that of propyl 1b and isopropyl 1c derivatives, which resulted in a notable activity decrease (Figure 1A). A slight increase of PET-inhibiting activity with further prolongation of the alkyl tail can be connected with the fact that a longer alkyl chain can be incorporated in the thylakoid membrane to a greater extent and subsequently cause membrane perturbation also at lower concentrations. The dependences of the PET-inhibiting activity log(1/IC50 [mol/L]) of compounds 2a–2h on clogP was bilinear, pentyl derivative 2e being the most effective PET inhibitor (Figure 1B). The lower activity of isopropyl derivative 2c could be connected with its lower aqueous solubility. The dependence of log(1/IC50 [mol/L]) on clogP for all the investigated compounds is illustrated in Figure 1C. It is evident that with the exception of compounds 1b and 1c of series I for compounds with clogP < 6.57 the activity of compounds of series II was slightly higher than that of compounds of series I with comparable lipophilicity. Lower PET-inhibiting activity of heptyl 2g and octyl 2h derivatives of series II compared to their analogues 1g, 1h of series I could be connected with their more significant solubility decrease with the elongation of the alkyl chain in the R2 substituent, resulting in precipitation from the solution during the experiment.
After exclusion of compounds 1a, 1b, and 2c, a bilinear course was found also for the dependences of the PET-inhibiting activity on log(1/IC50 [mol/L]) of cabamate series I and II in spinach chloroplasts on bulkiness expressed as molar volume MV of the alkyl tails R2, see Figure 2. The PET-inhibiting activity within the nitrated series II linearly increased with the increase of molar volume (influence of substituent R bulkiness, r = 0.9949, n = 4) up to pentyl derivative 2e (MV = 96.81 cm3). After this optimum, activity showed a strong linear decrease with the subsequent increase of molar volume up to MV = 146.33 cm3 (2h, r = −0.9923, n = 4). On the other hand, PET inhibition within the chlorinated series showed a moderate linear increase with the increase of molar volume (r = 0.9577, n = 5) up to heptyl derivative 1g (MV = 129.83 cm3) and, after that, slightly decreased to octyl derivative 1h (MV = 146.33 cm3).
It is important to note that a strong dependence of PET inhibition on the electron-withdrawing effect of substituents in individual series of many PET inhibitors was observed [14,15,16,34,49]. Therefore, it can be hypothesized that also a nitro moiety in the ortho position of the anilide ring (electronic Hammett’s parameter σ = 1.72 [50]) activates more strongly an amide bond—one of the structural motifs responsible for binding to PS II—and from this point of view, it is more advantageous than chlorine in the ortho position (electronic Hammett’s parameter σ = 0.67 [50]) of the anilide ring. In general, the N-alkyl tail of a suitable length facilitates penetration of a compound through hydrophobic regions of thylakoid membrane to the site of action in photosynthetic apparatus, as discussed below, but the electron-deficient amide bond is more important for the intrinsic effect of compounds [14,15,16,34,35,51]. Therefore, it is noteworthy that the PET-inhibiting activity of pentyl derivative 2e (IC50 = 0.233 mM, MV = 96.81 cm3) is similar to the PET inhibition of heptyl derivative 1g (IC50 = 0.263 mM, MV = 129.83 cm3) although MV value is significantly lower for compound 2e.
The dependence of PET-inhibiting activity of studied compounds 1a–1h and 2a–2h on Taft polar constants σ* of the alkyl tail R2 is shown in Figure 3. With the exception of compounds with the highest σ* values in both series belonging to compounds with short alkyl chains (ethyl 1a as well as ethyl 2a and propyl 2b derivatives), the observed trend for the two studied series was opposite. While for compounds of series I, the increasing σ* value resulted in increased inhibitory activity, for compounds of series II it showed a decrease. Therefore, it can be hypothesized that these different properties/behaviour of compounds of series I and II, as mentioned above, are caused by possible interactions and the electron activation of amide and carbamate groups (responsible also for interactions with the photosynthetic apparatus) with the spatially close NO2 moiety in the ortho position of the anilide ring.
Besides physicochemical parameters—for example, lipophilicity or electronic properties of substituents—an appropriate concentration of the compound at the site of action in the photosynthetic apparatus is also important for PET-inhibiting activity. A compound having very low aqueous solubility cannot pass through the hydrophilic regions of the thylakoid membrane to reach the site of action, which results in a significant decrease of inhibitory activity. The solubility of butyl derivative 1d and derivatives with longer alkyl chains was similar and significantly lower than that of propyl 1b and isopropyl 1c derivatives, which resulted in a notable activity decrease; a slight increase of PET-inhibiting activity with a further prolongation of the alkyl tail can be connected with the fact that a longer alkyl chain can be incorporated in the thylakoid membrane to a greater extent and subsequently cause membrane perturbation also at a lower concentration. This effect is connected with the surface activity of these compounds (they can be considered as non-ionic surfactants) and with the alkyl tail length (molar volume), which is again reflected by lipophilicity. From the aspect of PET-inhibiting activity, the lipophilicity optimum for C4–C8 alkyl chains can be found at C7 (compound 1g) and C5 (compound 2e), see Figure 1 and Figure 2. With the further elongation of the alkyl chain (hydrophobic part) to octyl, so called ‘cut-off’ effect—i.e., the loss/notable decrease of biological activity usually observed for amphiphilic compounds—was manifested [26,27,52,53,54].
The application of 2,5-diphenylcarbazide (DPC, artificial electron donor) that supplies electrons in the site of Z•/D• intermediate, i.e., tyrosine radicals TyrZ and TyrD (or their surroundings) that are situated in D1 and D2 proteins on the donor side of PS II [40] in chloroplasts, the activity of which was inhibited by the most active compounds 1b or 2e (up to 30% of the control), caused practically complete PET restoration already at the addition of three-fold DPC concentration with regard to the applied concentration of compound 2e. Therefore, it can be concluded that the site of action of studied alkylcarbamates, 1a–1h and 2a–2h, is situated mainly on the donor side of PS II. The site of action situated on the donor side of PS II was found also for 2-alkylthio-6-R-benzothiazoles (R = 6-formamido-, 6-acetamido-, and 6-benzoylamino-) [55], anilides of 2-alkylpyridine-4-carboxylic acids [56], cationic surfactants [57,58] acting in the intermediates Z•/D• and 2-alkylsulphanyl-4-pyridinecarbothioamides acting in the D• intermediate [59].

3. Experimental Section

3.1. Synthesis

Both pattern compounds N-(2-chlorophenyl)-2-hydroxynaphthalene-1-carboxamide (1) and N-(2-nitrophenyl)-2-hydroxynaphthalene-1-carboxamide (2) as well as all carbamates 1a–1h and 2a–2h were described recently by Gonec et al. [15,22].

3.2. Study of Photosynthetic Electron Transport (PET) Inhibition in Spinach Chloroplasts

Chloroplasts were prepared from spinach (Spinacia oleracea L.) according to Masarovicova and Kralova [60]. The PET inhibition in isolated spinach chloroplasts was performed as described recently [15] using the artificial electron acceptor 2,6-dichlorophenol-indophenol (DCPIP). The rate of photosynthetic electron transport was monitored as a photoreduction of DCPIP. The inhibitory efficiency of the studied compounds was expressed by IC50 values, i.e., by the molar concentration of the compounds causing a 50% decrease in the oxygen evolution rate relative to the untreated control. The comparable IC50 value for the selective herbicide 3-(3,4-dichlorophenyl)-1,1-dimethylurea, DCMU (Diuron®), was about 0.002 mmol/L. The results are summarized in Table 1.

3.3. Statistical Analysis

Statistical analyses were performed using a Statgraphics PlusCenturion XV (Herndon, VA, USA). All measurements were performed in triplicate. Data was expressed as mean ± standard deviation (SD). Analysis of variance (ANOVA) and the least significant difference (LSD) test were applied to determine differences between means. Differences were considered to be significant at p ≤ 0.05 confidence level. The one-way analysis of the variance (ANOVA) test was complemented by the Bonferroni’s multicomparison test.

4. Conclusions

A series of prepared and characterized eight 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates 1a–1h and eight 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates 2a–2h were tested for their activity related to the inhibition of PET in spinach (Spinacia oleracea L.) chloroplasts. The highest activity within both series of carbamates was observed for 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl propylcarbamate (1b, IC50 = 80 µM). In spite of the rather low PET-inhibiting activity of the compounds, it was found that they inhibit PET in PS II. Lipophilicity and bulkiness of N-alkyl substituent R2 seem to be important factors that influence PET-inhibiting activity, as trends for both series are similar. In addition to these parameters, PET-inhibiting activity was also affected by the electronic properties of R2 substituent (whereas the influence of PET inhibition on electronic properties for the two series was opposite), and by possible interactions and electron activation of amide and carbamate groups (responsible also for interactions with photosynthetic apparatus) with the spatially close NO2 and Cl moieties in the ortho position of the anilide ring.

Acknowledgments

This study was supported by IGA VFU Brno 320/2015/FaF and by the Slovak Research and Development Agency (Grant No. APVV-0516-12). The HPLC/HRMS system forms a part of the National Infrastructure CzeCOS ProCES CZ.02.1.01/0.0/0.0/16_013/0001609; Michal Oravec was supported by the National Sustainability Program (NPU I; Grant No. LO1415).

Author Contributions

Tomas Gonec, Josef Stranik, Jiri Kos, Josef Jampilek—design, synthesis of the compounds, SAR, writing of the paper. Michal Oravec—HPLC, HRMS, NMR analyses/characterizations of the compounds. Matus Pesko and Katarina Kralova—PET evaluation.

Conflicts of Interest

The authors declare no conflict of interest.

References and Notes

  1. Roth, H.J.; Fenner, H. Arzneistoffe, 3rd ed.; Deutscher Apotheker Verlag: Stuttgart, Germany, 2000. [Google Scholar]
  2. Kumar, S.; Kumar, P.; Sati, N. Synthesis and biological evaluation of Schiff bases and azetidinones of 1-naphthol. J. Pharm. Bioallied Sci. 2012, 4, 246–249. [Google Scholar] [CrossRef] [PubMed]
  3. Rokade, Y.B.; Sayyed, R.Z. Naphthalene derivatives: A new range of antimicrobials with high therapeutic value. Rasayan J. Chem. 2009, 2, 972–980. [Google Scholar]
  4. Durrant, J.D.; Hall, L.; Swift, R.V.; Landon, M.; Schnaufer, A.; Schnaufer, A.; Amaro, R.E. Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. Plos Negl. Trop. Dis. 2010, 4, e803. [Google Scholar] [CrossRef] [PubMed]
  5. Parineeta, B.N. Derivatives of 1-chloromethyl naphthalene: Synthesis and microbiological evaluation as potential antifungal agents. Der Pharma Chem. 2011, 3, 105–111. [Google Scholar]
  6. Kanno, T.; Tanaka, A.; Shimizu, T.; Nakano, T.; Nishizaki, T. 1-[2-(2-Methoxyphenylamino)ethylamino]-3-(naphthalene-1-yloxy)propan-2-ol as a potential anticancer drug. Pharmacology 2013, 91, 339–345. [Google Scholar] [CrossRef] [PubMed]
  7. Damu, G.L.V.; Wang, Q.P.; Zhang, H.Z.; Zhang, Y.Y.; Lv, J.S.; Zhou, C.H. A series of naphthalimide azoles: Design, synthesis and bioactive evaluation as potential antimicrobial agents. Sci. Chin. Chem. 2013, 56, 952–969. [Google Scholar] [CrossRef]
  8. Kauerova, T.; Kos, J.; Gonec, T.; Jampilek, J.; Kollar, P. Antiproliferative and pro-apoptotic effect of novel nitro-substituted hydroxynaphthanilides on human cancer cell lines. Int. J. Mol. Sci. 2016, 17, 1219. [Google Scholar] [CrossRef] [PubMed]
  9. Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.; Anderson, P.S. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235–2246. [Google Scholar] [CrossRef] [PubMed]
  10. Patchett, A.A.; Nargund, R.P. Chapter 26. Privileged structures—An update. Annu. Rep. Med. Chem. 2000, 35, 289–298. [Google Scholar]
  11. Klekota, J.; Roth, F.P. Chemical substructures that enrich for biological activity. Bioinformatics 2008, 24, 2518–2525. [Google Scholar] [CrossRef] [PubMed]
  12. Ji, T.; Lee, M.; Pruitt, S.C.; Hangauer, D.G. Privileged scaffolds for blocking protein-protein interactions: 1,4-disubstituted naphthalene antagonists of transcription factor complex HOX-PBX/DNA. Bioorg. Med. Chem. Lett. 2004, 14, 3875–3879. [Google Scholar] [CrossRef] [PubMed]
  13. Gonec, T.; Bobal, P.; Sujan, J.; Pesko, M.; Guo, J.; Kralova, K.; Pavlacka, L.; Vesely, L.; Kreckova, E.; Kos, J.; et al. Investigating the spectrum of biological activity of substituted quinoline-2-caboxamides and their isosteres. Molecules 2012, 17, 613–644. [Google Scholar] [CrossRef] [PubMed]
  14. Kos, J.; Zadrazilova, I.; Pesko, M.; Keltosova, S.; Tengler, J.; Gonec, T.; Bobal, P.; Kauerova, T.; Oravec, M.; Kollar, P.; et al. Antibacterial and herbicidal activity of ring-substituted 3-hydroxynaphthalene-2-carboxanilides. Molecules 2013, 18, 7977–7997. [Google Scholar] [CrossRef] [PubMed]
  15. Gonec, T.; Kos, J.; Zadrazilova, I.; Pesko, M.; Govender, R.; Keltosova, S.; Chambel, B.; Pereira, D.; Kollar, P.; Imramovsky, A.; et al. Antibacterial and herbicidal activity of ring-substituted 2-hydroxynaphthalene-1-carboxanilides. Molecules 2013, 18, 9397–9419. [Google Scholar] [CrossRef] [PubMed]
  16. Gonec, T.; Kos, J.; Zadrazilova, I.; Pesko, M.; Keltosova, S.; Tengler, J.; Bobal, P.; Kollar, P.; Cizek, A.; Kralova, K.; et al. Antimycobacterial and herbicidal activity of ring-substituted 1-hydroxynaphthalene-2-carboxanilides. Bioorg. Med. Chem. 2013, 21, 6531–6541. [Google Scholar] [CrossRef] [PubMed]
  17. Gonec, T.; Kos, J.; Nevin, E.; Govender, R.; Pesko, M.; Tengler, J.; Kushkevych, I.; Stastna, V.; Oravec, M.; Kollar, P.; et al. Preparation and biological properties of ring-substituted naphthalene-1-carboxanilides. Molecules 2014, 19, 10386–10409. [Google Scholar] [CrossRef] [PubMed]
  18. Gonec, T.; Zadrazilova, I.; Nevin, E.; Kauerova, T.; Pesko, M.; Kos, J.; Oravec, M.; Kollar, P.; Coffey, A.; O’Mahony, J.; et al. Synthesis and biological evaluation of N-alkoxyphenyl-3-hydroxynaphthalene-2-carboxanilides. Molecules 2015, 20, 9767–9787. [Google Scholar] [CrossRef] [PubMed]
  19. Kos, J.; Nevin, E.; Soral, M.; Kushkevych, I.; Gonec, T.; Bobal, P.; Kollar, P.; Coffey, A.; O’Mahony, J.; Liptaj, T.; et al. Synthesis and antimycobacterial properties of ring-substituted 6-hydroxynaphthalene-2-carboxanilides. Bioorg. Med. Chem. 2015, 23, 2035–2043. [Google Scholar] [CrossRef] [PubMed]
  20. Jampilek, J.; Clements, C.; Kos, J.; Gonec, T.; Gray, A.I. Synthesis and in vitro anti-trypanosomal screening of hydroxynaphthalene-2-carboxanilides. In Proceedings of the 6th Conversatory on Medicinal Chemistry, Lublin, Poland, 18–20 September 2014; p. 24 (K5). [Google Scholar]
  21. Gonec, T.; Pospisilova, S.; Kauerova, T.; Kos, J.; Dohanosova, J.; Oravec, M.; Kollar, P.; Coffey, A.; Liptaj, T.; Cizek, A.; et al. N-Alkoxyphenylhydroxynaphthalenecarboxamides and their antimycobacterial activity. Molecules 2016, 21, 1068. [Google Scholar] [CrossRef] [PubMed]
  22. Gonec, T.; Pospisilova, S.; Holanova, L.; Stranik, J.; Cernikova, A.; Pudelkova, V.; Kos, J.; Oravec, M.; Kollar, P.; Cizek, A.; et al. Synthesis and antimicrobial evaluation of 1-[(2-substituted phenyl)carbamoyl]naphthalen-2-yl carbamates. Molecules 2016, 21, 1189. [Google Scholar] [CrossRef] [PubMed]
  23. Jampilek, J.; Brychtova, K. Azone analogues: Classification, design, and transdermal penetration principles. Med. Res. Rev. 2012, 32, 907–947. [Google Scholar] [CrossRef] [PubMed]
  24. Laursen, J.S.; Engel-Andreasen, J.; Fristrup, P.; Harris, P.; Olsen, C.A. Cis-trans amide bond rotamers in β-peptoids and peptoids: Evaluation of stereoelectronic effects in backbone and side chains. J. Am. Chem. Soc. 2013, 135, 2835–2844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Zadrazilova, I.; Pospisilova, S.; Pauk, K.; Imramovsky, A.; Vinsova, J.; Cizek, A.; Jampilek, J. In vitro bactericidal activity of 4- and 5-chloro-2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2-yl]-benzamides against MRSA. BioMed Res. Int. 2015, 2015, 349534. [Google Scholar] [CrossRef] [PubMed]
  26. Zadrazilova, I.; Pospisilova, S.; Masarikova, M.; Imramovsky, A.; Monreal-Ferriz, J.; Vinsova, J.; Cizek, A.; Jampilek, J. Salicylanilide carbamates: Promising antibacterial agents with high in vitro activity against methicillin-resistant Staphylococcus aureus. Eur. J. Pharm. Sci. 2015, 77, 197–207. [Google Scholar] [CrossRef] [PubMed]
  27. Good, N.E. Inhibitors of the Hill reaction. Plant Physiol. 1961, 36, 788–803. [Google Scholar] [CrossRef] [PubMed]
  28. Kralova, K.; Sersen, F.; Cizmarik, J. Inhibitory effect of piperidinoethylesters of alkoxyphenylcarbamic acids on photosynthesis. Gen. Physiol. Biophys. 1992, 11, 261–267. [Google Scholar]
  29. Kralova, K.; Sersen, F.; Kubicova, L.; Waisser, K. Inhibitory effects of substituted benzanilides on photosynthetic electron transport in spinach chloroplasts. Chem. Pap. 1999, 53, 328–331. [Google Scholar] [CrossRef]
  30. Kralova, K.; Sersen, F.; Kubicova, L.; Waisser, K. Inhibition of photosynthetic electron transport in spinach chloroplasts by 3- and 4-halogeno substituted benzanilides and thiobenzanilides. J. Trace Microprobe Technol. 2000, 18, 251–256. [Google Scholar]
  31. Musiol, R.; Tabak, D.; Niedbala, H.; Podeszwa, B.; Jampilek, J.; Kralova, K.; Dohnal, J.; Finster, J.; Mencel, A.; Polanski, J. Investigating biological activity spectrum for novel quinoline analogues 2: Hydroxyquinolinecarboxamides with photosynthesis inhibiting activity. Bioorg. Med. Chem. 2008, 16, 4490–4499. [Google Scholar] [CrossRef] [PubMed]
  32. Otevrel, J.; Mandelova, Z.; Pesko, M.; Guo, J.; Kralova, K.; Sersen, F.; Vejsova, M.; Kalinowski, D.; Kovacevic, Z.; Coffey, A.; et al. Investigating the spectrum of biological activity of ring-substituted salicylanilides and carbamoylphenylcarbamates. Molecules 2010, 15, 8122–8142. [Google Scholar] [CrossRef] [PubMed]
  33. Imramovsky, A.; Pesko, M.; Monreal-Ferriz, J.; Kralova, K.; Vinsova, J.; Jampilek, J. Photosynthesis-inhibiting efficiency of 4-chloro-2-(chlorophenylcarbamoyl)phenyl alkyl-carbamates. Bioorg. Med. Chem. Lett. 2011, 21, 4564–4567. [Google Scholar] [CrossRef] [PubMed]
  34. Kralova, K.; Perina, M.; Waisser, K.; Jampilek, J. Structure-activity relationships of N-benzylsalicylamides for inhibition of photosynthetic electron transport. Med. Chem. 2015, 11, 156–164. [Google Scholar] [CrossRef] [PubMed]
  35. Jampilek, J.; Kralova, K.; Pesko, M.; Kos, J. Ring-substituted 8-hydroxyquinoline-2-carbox-anilides as photosystem II inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 3862–3865. [Google Scholar]
  36. Draber, W.; Tietjen, K.; Kluth, J.F.; Trebst, A. Herbicides in photosynthesis research. Angew. Chem. 1991, 3, 1621–1633. [Google Scholar] [CrossRef]
  37. Tischer, W.; Strotmann, H. Relationship between inhibitor binding by chloroplasts and inhibition of photosynthetic electron-transport. Biochim. Biophys. Acta 1977, 460, 113–125. [Google Scholar] [CrossRef]
  38. Trebst, A.; Draber, W. Structure activity correlations of recent herbicides in photosynthetic reactions. In Advances in Pesticide Science; Greissbuehler, H., Ed.; Pergamon Press: Oxford, UK, 1979; pp. 223–234. [Google Scholar]
  39. Bowyer, J.R.; Camilleri, P.; Vermaas, W.F.J. Herbicides, Topics in Photosynthesis; Baker, N.R., Percival, M.P., Eds.; Elsevier: Amsterdam, The Netherlands, 1991; Volume 10, pp. 27–85. [Google Scholar]
  40. Izawa, S. Acceptors and donors for chloroplast electron transport. In Methods in Enzymology; Part C; Colowick, P., Kaplan, N.O., Eds.; Academic Press: New York, NY, USA; London, UK, 1980; Volume 69, pp. 413–434. [Google Scholar]
  41. Pattabiraman, V.R.; Bode, J.W. Rethinking amide bond synthesis. Nature 2011, 480, 471–479. [Google Scholar] [CrossRef] [PubMed]
  42. Ghosh, A.K.; Brindisi, M. Organic carbamates in drug design and medicinal chemistry. J. Med. Chem. 2015, 58, 2895–2940. [Google Scholar] [CrossRef] [PubMed]
  43. Williamson, R.L.; Metcalf, R.L. Salicylanilides: A new group of active uncouplers of oxidative phosphorylation. Science 1967, 158, 1694–1695. [Google Scholar] [CrossRef] [PubMed]
  44. Renger, G. The action of 5-chloro-3-tert-butyl-2′-chloro-4′-nitro-salicylanilide and α,α-bis(hexafluoroacetonyl)aceton on the water-splitting enzyme system Y in spinach chloroplasts. FEBS Lett. 1975, 52, 30–32. [Google Scholar] [CrossRef]
  45. Black, C.C. Photosynthetic phosphorylation and associated reactions in the presence of a new group of uncouplers: Salicylanilides. Biochim. Biophys. Acta 1968, 162, 294–296. [Google Scholar] [CrossRef]
  46. Jampilek, J.; Dolezal, M.; Kunes, J.; Buchta, V.; Silva, L.; Kralova, K. Quinaldine derivatives: Preparation and biological activity. Med. Chem. 2005, 1, 591–599. [Google Scholar] [CrossRef] [PubMed]
  47. Musiol, R.; Jampilek, J.; Kralova, K.; Richardson, D.R.; Kalinowski, D.; Podeszwa, B.; Finster, J.; Niedbala, H.; Palka, A.; Polanski, J. Investigating biological activity spectrum for novel quinoline analogues. Bioorg. Med. Chem. 2007, 15, 1280–1288. [Google Scholar] [CrossRef] [PubMed]
  48. Jampilek, J. Potential of agricultural fungicides for antifungal drug discovery. Expert Opin. Drug Dis. 2016, 11, 1–9. [Google Scholar] [CrossRef] [PubMed]
  49. Imramovsky, A.; Pesko, M.; Jampilek, J.; Kralova, K. Synthesis and photosynthetic electron transport inhibition of 2-substituted 6-fluorobenzothiazoles. Monatsh. Chem. 2014, 145, 1817–1824. [Google Scholar] [CrossRef]
  50. Norrington, F.E.; Hyde, R.M.; Williams, S.G.; Wootton, R. Physiochemical-activity relations in practice. 1. A rational and self-consistent data bank. J. Med. Chem. 1975, 18, 604–607. [Google Scholar] [CrossRef] [PubMed]
  51. Pesko, M.; Kos, J.; Kralova, K.; Jampilek, J. Inhibition of Photosynthetic Electron Transport by 6-Hydroxynaphthalene-2-carboxanilides. Indian J. Chem. B 2015, 54B, 1511–1517. [Google Scholar]
  52. Balgavy, P.; Devinsky, F. Cut-off effects in biological activities of surfactants. Adv. Colloid Interface 1996, 66, 23–63. [Google Scholar] [CrossRef]
  53. Przestalski, S.; Sarapuk, J.; Kleszczynska, H.; Gabrielska, J.; Hladyszowski, J.; Trela, Z.; Kuczera, J. Influence of amphiphilic compounds on membranes. Acta Biochim. Pol. 2000, 47, 627–638. [Google Scholar] [PubMed]
  54. Sarapuk, J.; Kubica, K. Cut-off phenomenon. Cell. Mol. Biol. Lett. 1998, 5, 261–269. [Google Scholar]
  55. Kralova, K.; Sersen, F.; Sidoova, E. Effects of 2-alkylthio-6-aminobenzothiazoles and their 6-N-substituted derivatives on photosynthesis inhibition in Chlorella vulgaris and spinach chloroplasts. Gen. Phys. Biophys. 1993, 12, 421–427. [Google Scholar]
  56. Kralova, K.; Sersen, F.; Miletin, M.; Hartl, J. Inhibition of photosynthetic electron transport by some anilides of 2-alkylpyridine-4-carboxylic acids in spinach chloroplasts. Chem. Pap. 1998, 52, 52–58. [Google Scholar] [CrossRef]
  57. Kralova, K.; Sersen, F. Long chain bisquaternary ammonium salts-effective inhibitors of photosynthesis. Tenside Surfactant Deterg. 1994, 31, 192–194. [Google Scholar]
  58. Kralova, K.; Sersen, F.; Devinsky, F.; Lacko, I. Photosynthesis-inhibiting effects of cationic biodegradable gemini surfactants. Tenside Surfactant Deterg. 2010, 47, 288–293. [Google Scholar] [CrossRef]
  59. Kralova, K.; Sersen, F.; Klimesova, V.; Waisser, K. 2-Alkylsulphanyl-4-pyridine-carbothioamides–inhibitors of oxygen evolution in freshwater alga Chlorella vulgaris. Chem. Pap. 2011, 65, 909–912. [Google Scholar] [CrossRef]
  60. Masarovicova, E.; Kralova, K. Approaches to measuring plant photosynthesis activity. In Handbook of Photosynthesis, 2nd ed.; Pessarakli, M., Ed.; Taylor & Francis Group: Boca Raton, FL, USA, 2005; pp. 617–656. [Google Scholar]
Sample Availability: Samples of compounds 1–2h are available from author T. Gonec.
Molecules 22 01199 sch001 550
Scheme 1. Synthesis of 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl carbamates 1a–1h and 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl carbamates 2a–2h [22]. Reagents and conditions: (a) PCl3, chlorobenzene, MW; (b) TEA, acetonitrile, room temperature.
Scheme 1. Synthesis of 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl carbamates 1a–1h and 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl carbamates 2a–2h [22]. Reagents and conditions: (a) PCl3, chlorobenzene, MW; (b) TEA, acetonitrile, room temperature.
Molecules 22 01199 sch001
Molecules 22 01199 g001 550
Figure 1. Dependence of PET-inhibiting activity log(1/IC50 [mol/L]) of all discussed compounds 1a–1h (A), 2a–2h (B) and 1–2h (C) in spinach chloroplasts on lipophilicity expressed as clogP.
Figure 1. Dependence of PET-inhibiting activity log(1/IC50 [mol/L]) of all discussed compounds 1a–1h (A), 2a–2h (B) and 1–2h (C) in spinach chloroplasts on lipophilicity expressed as clogP.
Molecules 22 01199 g001
Molecules 22 01199 g002 550
Figure 2. Dependence of PET-inhibiting activity log(1/IC50 [mol/L]) of carbamates 1a–1h and 2a–2h in spinach chloroplasts on bulkiness of R2 substituents expressed as molar volume MV [cm−3] of alkyl tail of compounds.
Figure 2. Dependence of PET-inhibiting activity log(1/IC50 [mol/L]) of carbamates 1a–1h and 2a–2h in spinach chloroplasts on bulkiness of R2 substituents expressed as molar volume MV [cm−3] of alkyl tail of compounds.
Molecules 22 01199 g002
Molecules 22 01199 g003 550
Figure 3. Dependence of PET-inhibiting activity log (1/IC50 [mol/L]) of studied carbamates 1a–1h and 2a–2h on electronic properties expressed as Taft polar constants σ* of alkyl tail R2.
Figure 3. Dependence of PET-inhibiting activity log (1/IC50 [mol/L]) of studied carbamates 1a–1h and 2a–2h on electronic properties expressed as Taft polar constants σ* of alkyl tail R2.
Molecules 22 01199 g003
Table
Table 1. Structures of the discussed anilides 1, 2 and carbamates 1a–1h, 2a–2h; predicted clogP values, molar volume MV [cm−3], Taft polar constants σ* of R2 substituents of compounds and IC50 [mmol/L] values related to PET inhibition in spinach chloroplasts of tested compounds in comparison with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) standard. IC50 values are expressed as mean ± SD (n = 3 experiments), the means followed by different letters (a–j) are significantly different at p ≤0.05.
Table 1. Structures of the discussed anilides 1, 2 and carbamates 1a–1h, 2a–2h; predicted clogP values, molar volume MV [cm−3], Taft polar constants σ* of R2 substituents of compounds and IC50 [mmol/L] values related to PET inhibition in spinach chloroplasts of tested compounds in comparison with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) standard. IC50 values are expressed as mean ± SD (n = 3 experiments), the means followed by different letters (a–j) are significantly different at p ≤0.05.
Molecules 22 01199 i001
Comp.R1R2clogP ‡MVR2 ‡ [cm3]σ*R2 ‡PET Inhibition IC50 [mmol/L]
1Cl—5.03——0.049 ± 0.002 a
1aCl–C2H53.9447.29-0.110.659 ± 0.046 j
1bCl–C3H74.4163.80-0.120.080 ± 0.002 a
1cCl–CH(CH3)24.2064.18-0.190.271 ± 0.010 d
1dCl–C4H94.7180.31-0.250.589 ± 0.031 i
1eCl–C5H115.4796.81-0.230.396 ± 0.017 f
1fCl–C6H136.03113.32-0.250.358 ± 0.013 e
1gCl–C7H156.67129.83-0.230.263 ± 0.009 c,d
1hCl–C8H177.19146.33-0.230.290 ± 0.010 d
2NO2—4.45——0.121 ± 0.004 b
2aNO2–C2H53.5847.29-0.110.450 ± 0.022 g
2bNO2–C3H73.9663.80-0.120.365 ± 0.017 e,f
2cNO2–CH(CH3)23.8064.18-0.190.664 ± 0.041 j
2dNO2–C4H94.3280.31-0.250.274 ± 0.012 d
2eNO2–C5H115.1596.81-0.230.233 ± 0.008 c
2fNO2–C6H135.71113.32-0.250.283 ± 0.012 d
2gNO2–C7H156.81129.83-0.230.352 ± 0.018 e
2hNO2–C8H177.22146.33-0.230.487 ± 0.027 h
DCMU—————0.002
‡ calculated using ACD/Percepta ver. 2012 (Advanced Chemistry Development, Toronto, ON, Canada).

Share and Cite

MDPI and ACS Style

Gonec, T.; Stranik, J.; Pesko, M.; Kos, J.; Oravec, M.; Kralova, K.; Jampilek, J. Photosynthesis-Inhibiting Activity of 1-[(2-Chlorophenyl)carbamoyl]- and 1-[(2-Nitrophenyl)carbamoyl]naphthalen-2-yl Alkylcarbamates. Molecules 2017, 22, 1199. https://doi.org/10.3390/molecules22071199

AMA Style

Gonec T, Stranik J, Pesko M, Kos J, Oravec M, Kralova K, Jampilek J. Photosynthesis-Inhibiting Activity of 1-[(2-Chlorophenyl)carbamoyl]- and 1-[(2-Nitrophenyl)carbamoyl]naphthalen-2-yl Alkylcarbamates. Molecules. 2017; 22(7):1199. https://doi.org/10.3390/molecules22071199

Chicago/Turabian Style

Gonec, Tomas, Josef Stranik, Matus Pesko, Jiri Kos, Michal Oravec, Katarina Kralova, and Josef Jampilek. 2017. "Photosynthesis-Inhibiting Activity of 1-[(2-Chlorophenyl)carbamoyl]- and 1-[(2-Nitrophenyl)carbamoyl]naphthalen-2-yl Alkylcarbamates" Molecules 22, no. 7: 1199. https://doi.org/10.3390/molecules22071199

Article Metrics

Back to TopTop