Abstract
Ferrocene and its derivatives constitute versatile and interesting scaffolds for the global chemical enterprise due to its multiple applications that range from biomedical to materials science. Ferrocenyl derivatives are the leading compounds in our research for the syntheses and characterization as well as their potential biological applications. Among them, our recent focus has been in ferrocenyl chalcones as a framework for further derivatization. The proposed modifications consist on the incorporation of heterocyclic moieties into the ferrocenyl chalcone core. This can be afforded either by introducing a heterocyclic aromatic moiety as a substituent or functionalizing the α-β unsaturated system. Another modification explored is the formation of ammonium or pyridinium salts to increase water solubility. Studied ferrocenyl chalcones exhibit remarkable stability, physical, and electrochemical properties. These factors have led the approaches for them to be precursors of biologically active compounds (cancer, bacteria, malaria, and neurobiological diseases). Moreover, other potential applications include molecular materials, redox-sensors, and polymers. Our goal in this mini review is to highlight the chemistry of ferrocene derivatives with particular prominence to those ferrocenyl chalcones studied in our laboratory and their applications. Moreover, we are providing a background on ferrocene, chalcones, and ferrocenyl chalcones, emphasizing the methodologies with preeminent yields.
Ferrocene
Kealy and Pauson first synthesized Ferrocene in 1951 (Fig. 1) [1]. Its tridimensional structure, in which the Fe2+ ion is sandwiched between two cyclopentadienyl anions was determined by Woodward and Wilkinson in 1952 [2]. Fischer and coworkers also studied and confirmed the structure of ferrocene by nuclear magnetic resonance spectroscopy and X-ray crystallography [3]. Fischer focused his interest on the synthesis of several metallocenes [(M(C5H5)2], replacing iron by cobalt and nickel. In 1973 Fischer and Wilkinson were awarded the Nobel Prize for their contributions to organometallic chemistry. The discovery of ferrocene is a topic of discussion since Pauson et al. reported the synthesis first, but Miller reported to have done the work 3 years earlier [4]. Nevertheless, the discovery marked a novel contribution in organometallic chemistry by being the first organometallic sandwich structure ever reported.
Ferrocene.
Because of its structure, ferrocene soon attracted the attention of scientists. It is a small, non-toxic neutral metal complex, stable in air and water. Its aromaticity, ease of functionalization and reversible redox behavior of the metal center are some of the attractive features of ferrocene-based molecules as scaffolds for diverse applications. Ferrocene has been used as internal reference/standard in electrochemical experiments, as well as others ferrocene derivatives like decamethylferrocene, making it a molecule implemented in several experimental procedures [5], [6]. Since its discovery, ferrocene has remained at the forefront of organometallic chemistry as shown in Fig. 2.
Trends of publications related to ferrocene and its derivatives.
Every decade the number of publications related to ferrocene and its derivatives has substantially increased. However, the number has almost duplicated during the last 7 years. Among the multiple applications in electroactive materials, material sciences, biofuel cells, films, aerospace materials, surface science, biophysics, polymers, sensors, non-linear optical materials, catalysis, among others, its introduction to the field of bioinorganic chemistry has been the most remarkable and promising one [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Biomedical studies of organometallics have contributed novel therapeutic agents for devastating diseases as malaria, bacterial infections, cancer, fungus, and others.
Biological applications
Bacterial
Infections caused by bacteria are a serious problem for health. Although there are many antibiotics that can be effective, there is the limitation that bacteria create resistance. Therefore, the development of new therapeutic agents is necessary. One of the approaches to overcome the resistance of bacteria is to modify biologically active natural molecules with ferrocene and study their differences in bioactivity. Several ferrocenyl analogs of antibiotics have been synthesized and tested for antibacterial activity (Fig. 3) [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. Interestingly, in some instances, the antibiotic activity improved as is the case of penicillin and cephalosporin analogs reported by Edwards et al. They were the first to work on the substitution of a phenyl group by the ferrocene moiety [31], however, rifamycin analogs showed similar or lower activity [32].
Antibacterial compounds and their ferrocenyl analogs.
Malaria
Infections caused by parasites continue to be one of the leading causes of death in humans. Among these infections, malaria is one of the main global diseases caused by parasites in the world [33]. According to the 2017 Malaria Report of the World Health Organization (WHO), approximately 216 million clinical cases were reported showing an increase of about 5 million cases since 2015 of malaria, and 445 000 deaths in comparison to 438 000 for 2015 [34]. Plasmodium is the cause of malaria infections and is transmitted to humans by a female mosquito of the genus Anopheles. There are five types of Plasmodium species that can cause malaria in humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria and the simian Plasmodium knowlesi. Among these, the main source of life-threatening infections due to human malaria is Plasmodium falciparum [35], [36]. For many years, the most widely used medicine to treat malaria has been chloroquine due to its efficacy and accessibility [37]. Conversely, falciparum strains have developed resistance to chloroquine. This has sparked researchers’ interest in designing and developing new potential antimalarial drug that could be used along or combined with other drugs. An example is the combination therapy based on artemisinin. However, there are some disadvantages on this therapy: it is very expensive, it requires the use of other drugs, and it is administered by non-oral means [35], [36], [37], [38], [39]. Many researchers continue to be focused on exploring and synthesizing new compounds with antimalarial potential that could be more effective, quicker and less harmful to health. Among the compounds that have shown promising biological activity, there are ferrocene-containing compounds such as ferroquine as well as many others (Fig. 4) [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50]. Ferroquine is currently in an advanced phase of the clinical trial.
Antimalarial compounds and their ferrocenyl analogs.
Cancer
Cancer is the main global social health problem, being the second leading cause of death. According to the 2014 WHO report, approximately 14 million new cases and 8.2 million cancer-related deaths occurred in 2012. Regrettably, cases are expected to increase approximately 70% in the next two decades [53]. Recently the WHO International Agency for Research in Cancer (IARC) published that the global cancer burden is estimated to have risen to 18.1 million new cases and 9.6 million deaths in 2018 [54]. Currently, various treatments for cancer are used, including surgery, radiation, chemotherapy, hormones or immune therapies. Of these, the directed drug therapy is currently the most studied. Many researchers are focusing on the design and development of new therapeutic agents that could be highly selective for cancer cells and reduce the side effects of current therapies [55]. As aforementioned, ferrocene analogs of several known bioactive compounds and new compounds have been synthesized and studied (Fig. 5) [56], [57], [58], [59], [60], [61], [62], [63]. Although results have been varied, in many reported cases the presence of ferrocene replacing a phenyl group has drastically altered the effectiveness of compounds active against some types of cancer. For example, the common drugs used to treat breast cancer are tamoxifen and hydroxytamoxifen. These drugs have severe side effects that include blood clotting in the lungs and promote the development of resistance to the drug [64]. In ferrocifen, the ferrocene analog of tamoxifen and hydroxyfen, a phenyl group is replaced by the ferrocene moiety (Fig. 5). Jaouen and Metzler-Nolte varied the length of one of the carbon chains of the molecule and tested for antiproliferative activity. It was found that the addition of ferrocene to the drug increased its antiproliferative activity, specifically against hormone dependent and independent breast cancer cells [7]. A very interesting fact is that tamoxifen is not active against estrogen independent breast cancer cells, the activity presented by ferrocifen is attributed to the redox properties of the Fe+2 complex, leading to oxidative damage to DNA [65]. Although it has been reported that the substitution of aromatic moiety by ferrocene influences the solubility, lipophilicity and hydrophobicity, and that there are several structure-activity relationships (SAR) studies and proposals on mechanisms of action, there is still much to investigate to better understand the specific biochemical interaction of ferrocene producing its pharmacological effect [7], [66], [67], [68], [69], [70].
Biologically active compounds against cancer, and their ferrocenyl analogs.
Chalcones
Chalcones are natural occurring compounds of the flavonoid family, found in plants. These compounds consist of an α-β unsaturated ketone with two phenyl groups that can be found in both Z (cis) or E (trans) conformations. Chalcones have shown very diverse and significant biological activity related to the electron conjugation of the system since, when interrupted, the activity is essentially lost [74]. In fact, chalcones are precursors of flavonoids and isoflavones, which make them very important intermediates for the synthesis of many pharmaceuticals and heterocyclic compounds (Fig. 6) [75]. These properties make them a very popular synthetic target. Therefore, chalcones and their derivatives have been studied for years, reporting numerous compounds using various synthetic pathways.
Chalcones, precursors of flavones and isoflavones.
Essentially, the most popular method for the synthesis of chalcones consists on the condensation of the corresponding acetophenone and aromatic aldehydes via an Aldol or Claisen-Schmidt condensation [76]. Many parameters of these condensation reactions have been altered to find optimal reaction conditions. The traditional method includes the use of an acid or a base under reflux conditions. Nevertheless, not all reactions proceed under these conditions or provide high yields. Another approach is the solvent-free reaction, which usually results in higher yields and shorter reaction times [77]. Even though solvent free reactions provide a greener approach, labile reagents might oxidize or decompose under these conditions. To further improve the interactions between the corresponding starting materials, microwaves or sonication can be used and often allow reactions that do not proceed under the previously mentioned methods [78], [79]. The use of catalysts for Claisen-Schmidt condensations is also very common. Catalysts include: oxides, basic catalysts, ionic liquids, transition metal catalysts, among others [80], [81], [82], [83], [84]. Even though Aldol or Claisen-Schmidt condensations are the most common, other successful reactions have been reported. Some include Suzuki coupling, Heck, Julia–Kocienski olefination, Wittig olefination and Mannich reaction [85], [86], [87].
Chalcones and their derivatives exhibit biological activity towards a large array of bacteria and diseases. Chalcones have been modified on the search for potent drugs, commonly but not limited to replacing one of the phenyl groups with other aromatic substituents that show activity. Generally, a compound with more than one pharmacophore should be more active than its individual counterparts. Remarkable activity has been achieved in the treatment of cancer, malaria, HIV, Alzheimer’s disease, diabetes and as antimicrobials, anti-inflammatory and anti-oxidizing agents [88]. Chalcones bearing coumarin, colchicine, imines, furan rings, heterocyclic rings, and many other moieties have been reported with promising anti-cancer potential (Fig. 7) [74]. Coumarin-chalcones were reported with significant activity (IC50 from 3.59 to 8.12 μM) and selectivity to human cancer cell lines. Results showed that chloro groups at the para-position on the chalcone pharmacophore decreased selectivity to cancer cells, and that ester groups on the third position of the coumarin were essential for activity [89]. Chalcones bearing anthraquinones have also shown promising cytotoxicity (IC50 from 1.76 to 6.11 μM) and selectivity towards K562, HeLa, LS174, and A549 cancer cell lines [90], [91], [92]. Widely, hydroxyl and carbonyl groups were very common amongst substituents as well as electron withdrawing groups (nitro, cyano) mainly at the meta-positions, which increased anti-cancer activity in several cases. As anti-malaria agents, nitrogen containing heterocycles and methoxy bearing aryl groups have been resounding functionalities for the treatment of Chloroquine resistant strains of Plasmodium falciparum [93], [94]. Similar structural patterns followed for anti-bacterial, anti-inflammatory and antioxidant agents [95], [96]. Anti-HIV chalcones were highly substituted with electron donating groups, mainly methoxy [97], [98]. Chalcones are very versatile compounds both synthetically and bio-medically. As of now, two chalcone-based drugs have been approved (Fig. 8). Metochalcone, a choleretic drug and sofalcone, an anti-ulcer agent [98].
Skeleton of coumarin (a), anthraquinone (b), colchicine (c) and furan (d) based chalcones.
Chalcone based drugs clinically approved.
Ferrocenyl derivatives
Ferrocenyl derivatives have shown significant activity as anti-tumor agents to various types of cancers including breast, prostate and colon cancer [99]. Among the most studied groups of molecules for cancer activity are those containing multiple phenolic groups. Specifically, chalcones, flavonoids and stilbenes because of their antioxidant potential to trap free radicals [100]. Even though the role of ferrocene in the enhancement of biological activity is not fully understood, it is adjudicated to its physical and chemical properties, such as lipophilicity, size and reversible oxidation-reduction [101]. Building upon knowledge that organic chalcones exhibit biological activity, recent research reports that the substitution of one of the two-phenyl rings with a ferrocene group enhances their already observed biological activity. Ferrocenyl chalcones have shown significant activity as anti-tumor, anti-bacterial, and anti-plasmodium agents, among others [102].
Ferrocenyl chalcones
Ferrocenyl chalcones (Fig. 9) have been synthesized with a variety of substituents and synthetically transformed into other derivatives. Like the chalcones mentioned before, the ferrocenyl ones have been prepared by condensation reactions and other types of reactions, like couplings and olefinations [86]. In our research laboratory, a variety of ferrocenyl chalcones have been synthetized applying different approaches including green chemistry when possible. Our approaches for the Claisen-Schmidt condensation include solvent-free base catalyzed methods, and alcoholic base catalyzed media at room temperature or heat. In some cases, Stork’s approach at reflux was required to obtain the desired product.
Ferrocenyl chalcones general core.
The most traditional method reported in literature for the preparation of ferrocenyl chalcones, has been the ethanolic media Claisen-Schmidt condensation catalyzed by sodium or potassium hydroxide. The reactions time (from minutes to days) and yield (19–98) were variable as shown in the Table 1, depending of the aromatic ring and its substituents. The reported workup procedures include extraction, low-pressure solvent evaporation, column chromatography and recrystallization [42], [102], [103], [104], [105].
Reaction conditions for the synthesis of ferrocenyl chalcones using the Claisen-Schmidt condensation.
 |  | |||||
|---|---|---|---|---|---|---|
| G | Conditions | Time | Yield % | Conditions | Time | Yield % |
 | NaOH, EtOH, heat | 10 min | 96 [116] | NaOH, EtOH, H2O, rt | 24 h | 96 [117] |
| NaOH, rt (Solid-Phase) | 5–10 min | 96 [106] | ||||
 | KOH, MeOH, H2O, rt | >20 min | 43 [118] | KOH, MeOH, H2O, rt | >20 min | 56 [118] |
| Halogens | ||||||
 | KOH, EtOH, rt | 12 h | 85 [119] | KOH, EtOH, rt | >10 min | 92 [120] |
 | NaOH, EtOH, H2O, rt | 3 h | 70 [105], [121] | NaOH, EtOH, H2O rt | 24 h | 88b |
 | NaOH, EtOH, H2O, rt | 1 h | 89 [105], [121] | NaOH (Solvent-Free) | 5 min | 56b |
 | KOH, EtOH, rt | 5.5 h | 49 [122] | NaOH, EtOH, H2O rt | 24 h | 89b |
 | NaOH, EtOH, H2O, rt | 2.5 h | 40b | –a | –a | –a |
 | Al2O3 potassium fluoride-coated Solid-supported Catalyst, rt (Solvent-Free) | 4 min | 96 [111] | NaOH, EtOH, H2O, rt | 4 h | 86 [123] |
| NaOH, heat (Solvent-Free) | 10 min | 96 [106] | ||||
 | NaOH, EtOH, H2O Slightly heated | 24 h | 83 [102] | NaOH, EtOH, H2O Slightly heated | 24 h | 72 [102] |
 | NaOH, heat (Solvent-Free) | 24 h | 86–92 [124]d | NaOH, EtOH, H2O Slightly heated | 24 h | 85 [102] |
 | NaOH, EtOH, heat | 10 min | 98 [125]e | NaOH, EtOH, H2O, rt | 2.5 h | 96 [126] |
 | NaOH, EtOH, H2O, rt | 2 h | 96 [127] | NaOH, EtOH rt and cooled | 4 h | 90 [128] |
 | NaOH, EtOH, H2O, rt | 2 h | 90 [129] | –c | –c | –c |
| Nitrogen | ||||||
 | KOH, NiFe2O4 nanoparticles, EtOH, H2O rt (Catalyst) | 20 min | 97 [110] | KOH, EtOH, rt | >10 min | 90 [130] |
| Al2O3 potassium fluoride-coated Solid-supported Catalyst, rt Solid-State (Solvent-Free) | 3 min | 97 [111] | ||||
| KF adduct with alumina, Al2O3 potassium fluoride, EtOH, rt, (microwave-assisted/solid phase) | 3 min | 97 [131]e | ||||
 | NaOH, Bu4N+·-PF6, EtOH, heat | 4 h | 98 [132] | NaOH, rt (Solvent-Free) | 21 min | 90 [133] |
 | NaOH, EtOH | –c | 70e | NaOH, heat (Solvent-Free) | 1 h | 68 [134] |
 | NaOH, EtOH, H2O, rt | 3 h | 45b | –a | –a | –a |
 | NaOH, rt (Solvente-Free) | 30 min | 96 [106] | NaOH, EtOH, H2O, rt | 20 h | 42 [135], [115] |
 | –f | –f | –f | NaOH, rt (Solvent-Free) | 19 min | 93 [133] |
 | –f | –f | –f | NaOH, rt (Solvent-Free) | 14 min | 88 [133] |
 | NaOH Solvent-free [136] | –c | –c | NaOH, EtOH, rt | Overnight | 60–90 [137]d |
 | NaOH, EtOH, H2O, rt | 3.5 h | 38b | NaOH, EtOH, H2O, rt | 2 h | 68b |
| Oxygen | ||||||
 | Al2O3 potassium fluoride-coated Solid-supported Catalyst, rt Solid-State (Solvent-Free) | 7 min | 98 [138] | MeN+((CH2)7Me)3·Cl−, heated | 3.4 min | 94 [109]e |
 | KOH, NiFe2O4 nanoparticles, EtOH, H2O rt (Catalyst) | 25 min | 95 [139] | NaOH, EtOH rt and cooled | 4 h | 89 [128] |
| G | Conditions | Time | Yield % | Conditions | Time | Yield % |
 | NaOH, EtOH, H2O Slightly heated | 24 h | 89 [102] | NaOH, EtOH, H2O Slightly heated | 24 h | 80 [102] |
 | NaOH, EtOH, H2O rt | 24 h | 82b | KOH, EtOH, rt | 1–24 hd | 19 [45] |
 | Pyrrrolidine, Toluene, heat | 2 h | 27 [121] | KOH, EtOH, 0°C 0°C (1 h)→rt (72 h) nitrogen atmosphere | 73 h | 86 [140] |
 | NaOH, EtOH, heat | Overnight | 59–85 [141]d | NaOH, EtOH, heat | Overnight | 59–85 [141]d |
 | NaOH, EtOH, heat | 24 h | 27b | –a | –a | –a |
 | Pyrrolidine, Benzoate, CH2Cl2, heat | 24 h | 19b | –a | –a | –a |
| Indanone | ||||||
 | N/A | N/A | N/A | EtOH, NaOH, H2O heat→rt→ice cold water | 14.3 h | 98 [142] |
 | N/A | N/A | N/A | NaOH, EtOH, H2O, rt | 2 h | 85b |
aTo our knowledge they have not been reported. bNovel ferrocenyl chalcones synthetized by our research group. cNo conditions have been reported. dA range was reported. eReference and conditions reported from SciFinder. fThese products were obtained by the reduction of the corresponding nitro-substituted phenyl ferrocene compounds.
Moreover, other approaches for the Claisen-Schmidt condensation to produce ferrocenyl chalcones were widely implemented. Some of the research groups reported solid-phase conditions using Al2O3 and SiO2, and solvent-free conditions with or without microwave, or using ultrasound under catalytic conditions, like NiFe2O4 (nanoparticle), KF/Al2O3, or Aliquat 338. These reported alternate methods decreased the reaction time to 3–30 minutes (depending on the aromatic ring and its substituents) and the yields increased significantly to 83–98%. The workups reported also implement extractions followed by solvent evaporation and purification by recrystallization [106], [107], [108], [109], [110], [111], [112].
Based on the SciFinder database search, there is more than a 100 different ferrocenyl chalcones reported. Many research groups around the world have worked and reported the synthesis of the most common ferrocenyl chalcones like the one without substituents in the phenyl ring. For these reasons, we focus this part of our mini review in the ferrocenyl chalcone preparation by condensation approaches from acetylferrocene or ferrocenecarboxaldehyde with the corresponding aromatic aldehyde or ketone (Fig. 10). We summarize in the following tables (Tables 1 and 2) the reaction conditions and time for the highest yields reported in SciFinder [113] for each one of the ferrocenyl chalcones that have also been synthetized by our research group. As of our knowledge, fourteen of the ferrocenyl chalcones in the tables are novel and have only been synthesized in our laboratory.
General condensations synthetic scheme for ferrocenyl chalcones.
Heterocyclic ferrocenyl chalcones.
 |  | |||||
|---|---|---|---|---|---|---|
| G | Conditions | Time | Yield % | Conditions | Time | Yield % |
 | NaOH, EtOH, rt | 16 h | 98 [143] | KOH, EtOH, rt | 2 h | 90 [107] |
 | Microwave, Aliquat 336, hydrotalcite base agent | 4.5 min | 83 [109] | NaOH, EtOH, H2O, 30°C | 24 h | 74.5 [102] |
 | Microwave, Aliquat 336, hydrotalcite base agent | 4 min | 85 [109] | Microwave, Aliquat 336, hydrotalcite base agent | 3.3 min | 92 [109] |
 | Solvent-free, heat, NaOH | 30 min | 75b | –a | –a | –a |
 | Microwave, Aliquat 336, hydrotalcite base agent | 4 min | 83 [109] | Microwave, Aliquat 336, hydrotalcite base agent | 4.1 min | 90 [109] |
 | Solvent-free, heat, KOH | 30 min | 55b | –a | – | –a |
 | Solvent-free, NaOH | 6 min | 29b | –a | –a | –a |
aTo our knowledge they have not been reported. bNovel ferrocenyl chalcones synthetized by our research group.
All our novel compounds were characterized sustaining their structure and purity by 1H and 13C NMR, and FT-IR spectroscopy. There are characteristic 1H and 13C NMR chemical shifts for monosubstituted ferrocenyl chalcones which are present in all of our compounds with minimum variations depending on the substituent group. For the 1H NMR the ferrocenyl show shifts around 4–5 ppm, the aromatic and α,β-unsaturated alkene peaks are observed between 6 and 9 ppm, and the coupling constants (J) consistently ranged from 14 to 16 Hz, which confirms an E configuration of the alkene. When crystals were not obtained, we performed HRMS spectrometry and for the crystallized compounds the crystallographic structures were obtained. For example, the crystallographic structure of the ferrocenyl chalcone (E)-1-ferrocenyl-3-(2-methoxyphenyl)prop-2-en-1-one was reported by our research group [114].
We also explore the electrochemical properties of our ferrocenyl chalcones in collaboration with another research group. Using the electrochemical parameters obtained by the cyclic voltammetry we generalize some common aspects of the compounds and compare the two isomeric systems, 1-ferrocenyl (1-Fc) vs 3-Ferrocenyl (3-Fc). As we discussed in our previous publication, the ferrocenyl chalcone salts prepared from the pyridinyl chalcones in Table 2, showed a tendency for the formal redox potential (E°). The formal redox potential (E°) for the 1-Fc chalcones is higher than the formal redox potential for the 3-Fc compounds, suggesting an electronic effect caused by the proximity of the ferrocene to the carbonyl moiety [115].
We have also been working with ferrocenyl dichalcones. Ferrocenyl dichalcones can be prepared employing analogous methods for ferrocenyl mono chalcones from 1,1′-diacetylferrocene or 1,1′-ferrocenedicarboxaldehyde as shown in Fig. 11. The synthesis of these type of chalcones has been reported by a few research groups, but there is less variety of synthesized compounds and publications than for the ferrocenyl chalcones [144]. The most explored application of these compounds is for materials science and preparation of chemosensors. Some groups have focused their studies on the biological activity of these compounds as anticancer and radical scavenging agents [145], [146]. The syntheses reported also apply various basic catalyzed Claisen-Schmidt condensation approaches, as well as the use of microwave and solvent-free methods with variations in the temperature (low, room temperature, or heat) and concentration of the reactants. Those variations are focused on finding conditions that avoid the formation of side products (Figs. 12 and 13) [147], [148].
General condensations synthetic scheme for ferrocenyl dichalcones.
Non-symmetric ferrocenyl disubstituted chalcones byproduct.
Cyclic byproduct.
The aromatic ring in the ferrocenyl dichalcones reported by other research groups, include some of the G groups presented in the tables for the ferrocenyl mono chalcones such as phenyl, 2- and 4-chlorophenyl, 4-N,N-dimethylaminophenyl, 4-methoxyphenyl, 2-, 3-, and 4-nitrophenyl, 2-pyridyl among others [144], [145], [146], [147], [148]. We have also been working with most of the aromatic rings included in the previous tables for the preparation of ferrocenyl dichalcones and various of the products obtained are rather novel, such as the dichalcones of 3-pyridyl, 2-methoxyphenyl, and 4-acetamidophenyl.
Our research interest is also focused on Green Chemistry. For this reason, we have always tried to implement solvent-free approaches for the synthesis of our compounds, while possible, and tried to avoid harmful purification methods.
As mentioned at the beginning of this mini-review, our research group is not only focused on the synthesis and characterization of ferrocenyl chalcones. We have also studied in collaboration with other research groups, the possible applications of our compounds as potential biological active agents against Plasmodium bergei (for antimalarial bioassays), against various cancer cell lines MDA-MB-231 (non-estrogen dependent breast cancer), MCF-7 (estrogen-dependent breast cancer), PC-3 (prostate cancer), HeLa (cervix cancer), A-375 (melanoma), and against some bacterial strains like Escherichia coli and Staphylococcus aureus. We have also explored their applications as radical scavenging compounds and as biosensors. For example, the 4-benzyloxy-3-methoxyphenyl ferrocenyl chalcone shows an IC50 of 11.51 microM as radical scavenging in the DPPH assay and presents 34% of inhibition for the HeLa cell line after 24 h of incubation at 25 microM concentration.
As presented on the Scheme 1, in order to increase the potential of our compounds we derivatized the enone in the ferrocenyl chalcones to obtain new compounds. Moreover, we have further functionalized the substituents at the aromatic rings of the ferrocenyl chalcones. We implemented a nucleophilic attack to obtain quaternary amines from our nitrogen containing ferrocenyl chalcones and prepared 11 novel ferrocenyl chalcone amine salts. Nine of these salts exhibit high solubility in water. Water solubility is very important for our intention to develop new potential drugs, because many organometallic compounds with promising biological activity, including the ferrocenyl chalcones, are insoluble in water. For a compound to be useful clinically they have to be soluble at their biological absorption site [115].
Montes’ Laboratory Contributions: synthesis and characterization of ferrocenyl chalcones and derivatives, explore bioactivity, and improve methodologies by applying green chemistry principles.
Another explored modification is the use of ferrocenyl chalcones as monomeric units for the synthesis of polymers. With this in mind, acrylamide ferrocenyl chalcones were prepared from 4-amino ferrocenyl chalcones to obtain the monomer for the preparation of various polymers. Our main interest in ferrocene polymers is to obtain a broad range of properties by the incorporation of different functional groups within the monomeric units in order to enhance the electrochemical properties of the monomers and expand the ability to donate electrons, to explore their potential applications as multi stimuli responsive biosensors. The synthetic steps include chemioselective reduction of nitro containing precursors, amidation of a phenylamine substrate and its radical polymerization reaction to obtain co- and terpolymers. Ferrocenyl chalcone derivatives have been obtained with yields that vary from 65% to 86%, while polymers have been obtained from 64% to 76%. The characterization of these polymers was achieved using, IR spectroscopy, UV-Vis spectroscopy, and electrochemical techniques. Uses for such types of polymers include: light emitting diodes, electrochemical sensors, thin film transistors, and liquid crystals [149], [150], [151]. Another application for ferrocene polymers is the development of supramolecular gels that are stimuli responsive in order to improve drug delivery methods and biosensing capabilities [152].
An ongoing research in our group is focused on some known biologically active compounds such as curcumin, cannabidiol (CBD), and pentamidine. Curcumin has shown antioxidant, antimalarial, anti-tumoral, anti-inflammatory, antimicrobial, among others properties [153]. CBD has shown different pharmacological effects, working for inflammatory, neurodegenerative diseases and cancer [154]. Pentamidine has proved to be a very effective antimalarial, antifungal, antiparasitic and antibacterial agent [155]. For these reasons we are working on the syntheses of ferrocenyl analogs of these natural products.
Conclusion
We present an overview on ferrocene and some of its derivatives, focusing on ferrocenyl chalcones’ potential applications, and synthetic approaches. This converges with our research area of interest, which contributes to: the synthesis of novel ferrocenyl chalcones; the improvement of synthetic methodology; the examination of subsequent derivatizations and relevant characteristics; and the possible biomedical and materials applications. The chemistry of ferrocene and its derivatives is a fascinating area of research that is still under developed. There are many research questions to be answered, and a broad spectrum of applications to be explored. Ferrocene will and should continue inspiring researchers to design and synthesize derivatives, especially drugs with higher efficiency toward devastating diseases.
Funding source: National Institutes of Health
Award Identifier / Grant number: 5T34GM007821-38
Funding source: Foundation for the National Institutes of Health
Award Identifier / Grant number: 5R25GM061151
Funding statement: We gratefully acknowledge the contributions of former and current members of Montes’ group. To Dr. Dalice Piñero and Dr. José A. Prieto for their help and suggestions and Dr. Carolyn Ribes and Dr. Angela Wilson for their kind invitation to contribute this mini-review. This work was supported by the National Institutes of Health MARC (5T34GM007821-38) RISE, Foundation for the National Institutes of Health, Funder Id: 10.13039/100000009 (5R25GM061151) and NASA Puerto Rico Space Grant (NASA-PRSP) grants.
References
[1] T. J. Kealy, P. L. Pauson. Nature168, 1039 (1951).10.1038/1681039b0Search in Google Scholar
[2] G. Wilkinson, M. Rosenblum, M. C. Whiting, R. B. Woodward. J. Am. Chem. Soc.74, 2125 (1952).10.1021/ja01128a527Search in Google Scholar
[3] E. O. Fischer, W. Z. Pfab. Naturforsch7b, 377 (1952).10.1515/znb-1952-0701Search in Google Scholar
[4] S. A. Miller, J. A. Tebboth, J. F. Tremaine. J. Chem. Soc.0, 632 (1952).10.1039/jr9520000632Search in Google Scholar
[5] P. Stepnicka. Ferrocenes: Ligands, Materials and Biomolecules, Wiley, England (2008).Search in Google Scholar
[6] I. Noviandri, K. N. Brown, D. S. Fleming, P. T. Gulyas, P. A. Lay, A. F. Masters, L. Phillips. J. Phys. Chem. B103, 6713 (1999).10.1021/jp991381+Search in Google Scholar
[7] G. Jaouen, N. Metzler-Nolte. Medicinal Organometallic Chemistry, Springer-Verlag, Berlin Heidelberg (2010).10.1007/978-3-642-13185-1Search in Google Scholar
[8] G. Jaouen. Bioorganometallics, Biomolecules, Labeling, Medicine, Wiley, England (2006).10.1002/3527607692Search in Google Scholar
[9] G. Jaouen, M. Salmain, Bioorganometllic Chemistry, Applications in Drug Discovery, Biocatalysis, and Imaging, Wiley, England (2015).Search in Google Scholar
[10] E. Alessio. Bioinorganic Medicinal Chemistry, Wiley, England (2011).10.1002/9783527633104Search in Google Scholar
[11] M. Gielen, E. Tiekink. Metallotherapeutic Drugs and Metal-Base Diagnostic Agents, The use of Metals in Medicines, Wiley, England (2005).10.1002/0470864052Search in Google Scholar
[12] F. Ali Larik, A. Saeed, T. Abdul Fattah, U. Muqadar, P. Ali Channar. Appl. Organomet. Chem.31, 1 (2016).10.1002/aoc.4008Search in Google Scholar
[13] B. Albada, N. Metzzler-Nolte. Chem. Rev.116, 11767 (2016).10.1021/acs.chemrev.6b00166Search in Google Scholar
[14] M. Patra, G. Gasse. Nat. Rev. Chem.1, 66 (2017).10.1038/s41570-017-0066Search in Google Scholar
[15] D. van Staveren, N. Metzler-Nolte. Chem. Rev.104, 5931 (2004).10.1021/cr0101510Search in Google Scholar PubMed
[16] E. Lewandowski, L. Szczupak, S. Wong, J. Skiba, A. Guspiel, J. Solecka, V. Vrcek, K. Kowalski, Y. Chen. Organometallics39, 1673 (2016).10.1021/acs.organomet.6b00888Search in Google Scholar PubMed PubMed Central
[17] R. GuL, Z. Nawaz, A. Badshah, A. Khan, A. Junaid, R. Naz, M. Kamran Rauf, S. Hayat. J. Drug. Design. Med. Chem.2, 35 (2016).10.11648/j.jddmc.20160204.11Search in Google Scholar
[18] E. Njogu, B. Omondi, V. Nyamori. S. Afr. J. Chem.69, 51 (2016).10.17159/0379-4350/2016/v69a7Search in Google Scholar
[19] M. Görmen, S. Sylla-Iyarreta Veitía, F. Trigui, M. El Arbi, C. Ferroud. J. Organomet. Chem.794, 274 (2015).10.1016/j.jorganchem.2015.07.016Search in Google Scholar
[20] S. Yavuz, H. Yildirim. J. Chem.2013, 1 (2013).10.1155/2013/149693Search in Google Scholar
[21] S. Ali, A. Badshah, A. Ali Ataf, I. Din, B. Lal, K. Mohammed Khan. Med. Chem. Res.22, 3154 (2013).10.1007/s00044-012-0311-8Search in Google Scholar
[22] K. Kowalski, J. Skiba, L. Oehnnger, I. Ott, J. Solecka, A. Rajnisz, B. Therrien. Organometallics32, 5766 (2013).10.1021/om400294sSearch in Google Scholar
[23] K. Tiwari, J. Monserrat, A. Hequet, C. Ganem-Elbaz, T. Cresteil, G. Jaouen, A. Vessieres, E. Hillard, C. Jolivalt. Dalton. T.41, 645 (2012).10.1039/c2dt12180hSearch in Google Scholar
[24] J. Skiba, A. Rajnisz, K. Navakoski de Oliveira, I. Ott, J. Solecka, K. Kowalski. Eur. J. Med. Chem.57, 234 (2012).10.1016/j.ejmech.2012.09.023Search in Google Scholar PubMed
[25] G. Maguene, J. Jakhlal, M. Ladyman, A. Vallin, D. A. Ralambomanana, T. Bousquet, J. Maugein, J. Lebibi, L. Pelinski. Eur. J. Med. Chem.46, 31 (2011).10.1016/j.ejmech.2010.10.004Search in Google Scholar PubMed
[26] B. Long, C. He, Y. Yang, J. Xiang. Eur. J. Med. Chem.45, 1181 (2010).10.1016/j.ejmech.2009.12.045Search in Google Scholar PubMed
[27] M. Patra, G. Gasser, M. Wenzel, K. Merz, J. Bandow, N. Metzler-Nolte. Organometallics29, 4312 (2010).10.1021/om100614cSearch in Google Scholar
[28] M. Zabic, Z. Kukric, L. Topallic-Trivunovic. Chem. Ind. Chem. Eng. Q.15, 251 (2009).10.2298/CICEQ0904251ZSearch in Google Scholar
[29] M. El Arbi, P. Pigeon, S. Top, A. Rhouma, S. Aifa, A. Rebai, M. Vessieres, A. Plamont, G. Japuen. J. Organomet. Chem.696, 1038 (2011).10.1016/j.jorganchem.2010.09.015Search in Google Scholar
[30] I. Damljanovic, N. Vukicevic, N. Radulovic, R. Palic, E. Ellmerer, M. Ratkovic, M. Joksovic, R. Vukicevic. Bioorg. Med Chem. Lett.19, 1093 (2009).10.1016/j.bmcl.2009.01.006Search in Google Scholar PubMed
[31] F. Edwards, R. Epton, G. J. Marr. J. Organomet Chem.85, 23 (1975).10.1016/S0022-328X(00)80708-1Search in Google Scholar
[32] D. Scutaru, L. Tataru, I. Mazilu, M. Vata, T. Lixandru, C. Simionescu. Appl. Organomet. Chem.7, 225 (1993).10.1002/aoc.590070402Search in Google Scholar
[33] J. Ontoria, G. Paonessa, S. Penzi, F. Ferrigno, E. Nizi, L. Biancolfiore, S. Melancona, R. Graziani, D. Roberts, P. Willis, A. Bresciani, N. Gennari, O. Cecchetti, E. Monteagudo, M. Orsale, M. Veneziano, A. Di Marco, A. Cellucci, R. Laufer, S. Altamura, V. Summa, S. Harper. ACS Med. Chem. Lett.7, 454 (2016).10.1021/acsmedchemlett.5b00468Search in Google Scholar PubMed PubMed Central
[34] WHO. World Malaria Report 2015: Summary. World Health Organization http://www.who.int/malaria/publications/world-malaria-report-2017/en/ (accessed, July 13, 2018).Search in Google Scholar
[35] C. Orvig, C. Hermann, P. F. Salas. Chem. Rev.113, 3450 (2013).10.1021/cr3001252Search in Google Scholar PubMed
[36] M. A. Biamonte, J. Wanner, K. G. Le Roch. Bioorg. Med. Chem. Lett.23, 2829 (2013)10.1016/j.bmcl.2013.03.067Search in Google Scholar PubMed PubMed Central
[37] R. Raj, A. Saini, J. Gut, P. J. Rosenthal, V. Kumar. Eur. J. Med. Chem.95, 230 (2015).10.1016/j.ejmech.2015.03.045Search in Google Scholar PubMed
[38] R. Chopra, C. de Kock, P. Smith, K. Chibale, K. Singh. Eur. J. Med. Chem.100, 1 (2015).10.1016/j.ejmech.2015.05.043Search in Google Scholar PubMed
[39] A. Singh, J. Gut, P. Rosenthal, V. Kumar. Eur. J. Med. Chem.125, 269 (2017).10.1016/j.ejmech.2016.09.044Search in Google Scholar PubMed
[40] A. Wilhelm, L. Gibhard, K. Pravin, E. Abay, K. Swart, N. Lawrence, R. Khoury, J. van de Westhulzen, P. Smith, L. Wiesners. J. Nat. Prod.78, 1848 (2015).10.1021/acs.jnatprod.5b00114Search in Google Scholar
[41] F. J. Smit, J. J. Bezuidenhout, C. C. Bezuidenhout, D. David. Med. Chem. Res.25, 568 (2016).10.1007/s00044-016-1509-ySearch in Google Scholar
[42] X. Wu, P. Wilairat, M. Go. Bioorg. Med. Chem. Lett.12, 2299 (2002).10.1016/S0960-894X(02)00430-4Search in Google Scholar
[43] T. Itoh, S. Shirakami, N. Ishida, Y. Yamashita, T. Yoshida, H. Kim, Y. Wataya. Bioorg. Med. Chem. Lett.10, 1657 (2000).10.1016/S0960-894X(00)00313-9Search in Google Scholar
[44] J. Guillon, E. Mouray, C. Moreau, I. Forfar, V. Desplat, S. Belisle-Fabre, N. Pinaud, F. Ravanello, A. Le-Naour, J. Leger, G. Gosmann, C. Jarry, G. Deleis, P. Sonnet, P. Grellier. Eur. J. Med. Chem.46, 2310 (2011).10.1016/j.ejmech.2011.03.014Search in Google Scholar
[45] X. Wu, E. Tiekink, J. Kostetski, N. Kocherginsky, A. Tan, S. Khoo, P. Wilairat, M. Go. Eur. J. Med. Chem.27, 175 (2006).10.1016/j.ejps.2005.09.007Search in Google Scholar
[46] C. Roux, C. Biot. Future. Med. Chem.4, 783 (2012).10.4155/fmc.12.26Search in Google Scholar
[47] J. McCarthy, T. Rückle, E. Djeriou, C. Cantalloube, D. Ter-Minassian, M. Baker, P. O’Rourke, L. Marquart, R. Hooft van Huijsduijnene, J. Möhrle. Malaria. J.15, 469 (2016).10.1186/s12936-016-1511-3Search in Google Scholar
[48] J. Matos, N. Vale, M. Collins, J. Gut, P. Rosenthal, M. Cushion, R. Moreira, P. Gomes. Med. Chem. Comm.1, 199 (2010).10.1039/c0md00082eSearch in Google Scholar
[49] N. Bellotti de Souza, A. Campos, A. Cabral de Oliveira, S. Top, P. Pigeon, G. Jaouen, M. Fonseca Goulart, A. Ursine Krettli. Mem. Inst. Oswaldo Cruz.110, 981 (2015).10.1590/0074-02760150163Search in Google Scholar
[50] K. Chivale, J. Moss, M. Blackie, P. vanSchalkwyk Smith. Tetrahedron Lett.41, 6231 (2000).10.1016/S0040-4039(00)01036-4Search in Google Scholar
[51] C. de Lange, D. Coertzen, F. J. Smit, J. F. Wentzel, H. N. Wong, L. M. Birkholtz, R. K. Haynes, D. D. N’Da. Bioorg. Med. Chem. Lett.28, 289 (2018).10.1016/j.bmcl.2017.12.057Search in Google Scholar PubMed
[52] C. Biot, J. Dessolin, I. Ricard, D. Dive. J. Organomet. Chem.689, 4678 (2004).10.1016/j.jorganchem.2004.04.036Search in Google Scholar
[53] WHO. World Cancer Report 2014, World Health Organization, Lyon (2014). http://www.who.int/cancer/publications/WRC_2014/en/.Search in Google Scholar
[54] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jemal. CA-Cancer. J. Clin.68, 394 (2018).10.3322/caac.21492Search in Google Scholar PubMed
[55] K. R. Siegel, K. Miller, C. Chieh, A. Mariorro, J. Kramer, J. Rowland, K. Stein, R. Alteri, A. Jemal. CA-Cancer. J. Clin.66, 7 (2016).10.3322/caac.21332Search in Google Scholar PubMed
[56] K. Kowalski, L. Szczupak, L. Oehninger, I. Ott, P. Hikisz, A. Koceva-Chyla, B. Therrien. J. Organomet. Chem.772–773, 49 (2014).10.1016/j.jorganchem.2014.08.027Search in Google Scholar
[57] C. M. P. Pereira, D. Venzke, G. H. G. Trossini. Quim. Nova36, 143 (2013).10.1590/S0100-40422013000100024Search in Google Scholar
[58] S. Shen, J. Shao, J. Liu, J. Miao, B. Zhao. Eur. J. Med. Chem.63, 256 (2013).10.1016/j.ejmech.2013.02.016Search in Google Scholar PubMed
[59] M. Chalal, D. Delmas, P. Meunier, N. Latruffe, D. Vervandier-Fasseur. Molecules19, 7850 (2014).10.3390/molecules19067850Search in Google Scholar PubMed PubMed Central
[60] B. Biersack, A. Ahmad, K. Mahal, S, Padhye, F. Sarkar, R. Schobert. J. Saudi Chem. Soc.21, 105 (2017).10.1016/j.jscs.2016.03.005Search in Google Scholar
[61] H. Nguyen, A. A. Sallustrau, J. Balzarini, M. Bedford, J. Eden, N. Georgousi, N. Hodges, J. Kedge, Y. Mehellou, C. Tselepis, J. Tucker. J. Med. Chem.57, 5817 (2014).10.1021/jm500246hSearch in Google Scholar PubMed
[62] A. Arezki, G. Chabot, L. Quentin, D. Scherman, G. Jaouen, E. Brulé. Med. Chem. Com.2, 190 (2011).10.1039/c0md00231cSearch in Google Scholar
[63] J. Yong, C. Lu, X. Wu. Med. Chem. Commun.5, 968 (2014).10.1039/c4md00151fSearch in Google Scholar
[64] J. Cuzick, T. Powles, U. Veronesi, J. Forbes, R. Edwards, S. Ashley, P. Boyle. Lancet361, 296 (2003).10.1016/S0140-6736(03)12342-2Search in Google Scholar
[65] S. H. van Rijt, P. J. Sadler. Drug Discov. Today14, 1089 (2009).10.1016/j.drudis.2009.09.003Search in Google Scholar PubMed PubMed Central
[66] A. Nguyen, A. Vessiéres, E. Hillard, S. Top, P. Pigeon, G. Jaouen. Chimia61, 716 (2007).10.2533/chimia.2007.716Search in Google Scholar
[67] V. Kumar, K. Kumar, S. Carrére-Kremer, L. Kremer, Y. Guérardel, C. Biot. Organometallics32, 5713 (2013).10.1021/om301157zSearch in Google Scholar
[68] Y. Li, H. Ma, L. Han, W. Liu, B. Zhao, S. Zhang, J. Miao. Acta Pharmacol. Sin.34, 960 (2013).10.1038/aps.2013.19Search in Google Scholar PubMed PubMed Central
[69] A. Leonidova, P. Anstaett, V. Pierroz, C. Mari, B. Spingler, S. Ferrari, G. Gasser. Inorg. Chem.54, 9740 (2015).10.1021/acs.inorgchem.5b01332Search in Google Scholar PubMed
[70] G. Jaouen, A. Vessieres, S. Top. Chem. Soc. Rev.44, 8802 (2015).10.1039/C5CS00486ASearch in Google Scholar
[71] G. Gasser, I. Ott, N. Metzler-Nolte. J. Med. Chem.54, 3 (2011).10.1021/jm100020wSearch in Google Scholar PubMed PubMed Central
[72] M. Beaupérin, D. Polat, F. Roudesly, S. Top, A. Vessières, J. Oble, G. Jaouen, G. Poli. J. Organomet. Chem.839, 83 (2017).10.1016/j.jorganchem.2017.02.005Search in Google Scholar
[73] A. Wieczorek, A. Blauż, A. Żal, H. J. Aranshahi, J. Reynisson, C. G. Hartinger, B. Rychlik, D. Plażuk. Chem. Eur. J.22, 11413 (2016).10.1002/chem.201601809Search in Google Scholar
[74] P. Singh, A. Anand, V. Kumar. Eur. J. Med. Chem.85, 758 (2014).10.1016/j.ejmech.2014.08.033Search in Google Scholar
[75] D. Powers, D. Casebier, D. Fokas, W. Ryan, J. Troth, D. Coffen. Tetrahedron54, 4085 (1998).10.1016/S0040-4020(98)00137-9Search in Google Scholar
[76] A. Modzelewska, C. Pettit, G. Achanta, N. Davidson, P. Huang, S. Khan. Bioorgan. Med. Chem.14, 3491 (2006).10.1016/j.bmc.2006.01.003Search in Google Scholar
[77] V. Calvino, M. Picallo, A. J. López-Peinado, R. M. Martín-Aranda, C. J. Durán-Valle. Appl. Surf. Sci.252, 6071 (2006).10.1016/j.apsusc.2005.11.006Search in Google Scholar
[78] M. Ahmad, V. Sastry, N. Bano, S. Anwar. Arab. J. Chem.9, S931 (2016).10.1016/j.arabjc.2011.09.002Search in Google Scholar
[79] J. T. Li, W. Z. Yang, S. X. Wang, S. H. Li, T. S. Li. Ultrason. Sonochem.9, 237 (2002).10.1016/S1350-4177(02)00079-2Search in Google Scholar
[80] S. Toledo-Flores, R. Portillo, G. Angel, R. Gómez. React. Kinet. Catal. L.92, 361 (2007).10.1007/s11144-007-5188-zSearch in Google Scholar
[81] S. Saravanamurugan, M. Palanichamy, B. Arabindoo, V. Murugesan. Catal. Commun.6, 399 (2005).10.1016/j.catcom.2005.03.005Search in Google Scholar
[82] H. Qian, D. Liu, C. Lv. Ind. Eng. Chem. Res.50, 1146 (2011).10.1021/ie101790kSearch in Google Scholar
[83] D. Kumar, S. Suresh, J. Sandhu. Green. Chem. Lett. Rev.3, 283 (2010).10.1080/17518251003776893Search in Google Scholar
[84] F. Dong, C. Jian, F. Zhenghao, G. Kai, L. Zuliang. Catal. Commun.9, 1924 (2008).10.1016/j.catcom.2008.03.023Search in Google Scholar
[85] S. Eddarir, N. Cotelle, Y. Bakkour, C. Rolando. Tetrahedron. Lett.44, 5359 (2003).10.1016/S0040-4039(03)01140-7Search in Google Scholar
[86] A. Kumar, S. Sharma, V. Tripathi, S. Srivastava. Tetrahedron66, 9445 (2010).10.1016/j.tet.2010.09.089Search in Google Scholar
[87] C. Xu, G. Chen, X. Huang. Org. Prep. Proced. Int.27, 559 (1995).10.1080/00304949509458500Search in Google Scholar
[88] C. Zhuang, W. Zhang, C. Sheng, W. Zhang, C. Xing, Z. Miao. Chem. Rev.117, 7762 (2017).10.1021/acs.chemrev.7b00020Search in Google Scholar PubMed PubMed Central
[89] K. Sashidhara, A. Kumar, M. Kumar, J. Sarkar, S. Sinha. Bioorg. Med. Chem. Lett.20, 7205 (2010).10.1016/j.bmcl.2010.10.116Search in Google Scholar PubMed
[90] T. Stanojković, V. Marković, I. Matić, M. Mladenović, N. Petrović, A. Krivokuća, M. Petković, M. Joksović. Bioorg. Med. Chem. Lett.28, 2593 (2018).10.1016/j.bmcl.2018.06.048Search in Google Scholar PubMed
[91] B. Kolundžija, V. Marković, T. Stanojković, L. Joksović, I. Matić, N. Todorović, M. Nikolić, M. Joksović. Bioorg. Med. Chem. Lett.24, 65 (2014).10.1016/j.bmcl.2013.11.075Search in Google Scholar PubMed
[92] S. Khatib, O. Nerya, R. Musa, M. Shmuel, S. Tamir, J. Vaya. Bioorg. Med. Chem.13, 433 (2005).10.1016/j.bmc.2004.10.010Search in Google Scholar
[93] R. Li, G. L. Kenyon, F. E. Cohen, X. Chen, B. Gong, J. N. Dominguez, E. Davidson, G. Kurzban, R. E. Miller, E. O. Nuzum. J. Med. Chem.38, 5031 (1995).10.1021/jm00026a010Search in Google Scholar
[94] S. Awasthi, N. Mishra, B. Kumar, M. Sharma, A. Bhattacharya, L. Mishra, V. Bhasin. Med. Chem. Res.18, 407 (2009).10.1007/s00044-008-9137-9Search in Google Scholar
[95] B. Bandgar, S. Patil, R. Gacche, B. Korbad, B. Hote, S. Kinkar, S. Jalde. Bioorg. Med. Chem. Lett.20, 730 (2010).10.1016/j.bmcl.2009.11.068Search in Google Scholar
[96] K. V. Sashidhara, K. Bhaskara Rao, P. Kushwaha, R. K. Modukuri, P. Singh, I. Soni, P. K. Shukla, S. Chopra, M. Pasupuleti. ACS Med. Chem. Lett.6, 809 (2015).10.1021/acsmedchemlett.5b00169Search in Google Scholar
[97] S. Fatima, A. Sharma, R. Saxena, R. Tripathi, S. Shukla, S. Pandey, R. Tripathi, R. Tripathi. Eur. J. Med. Chem.55, 195 (2012).10.1016/j.ejmech.2012.07.018Search in Google Scholar
[98] J. H. Wu, X. H. Wang, Y. H. Yi, K. H. Lee. Bioorg. Med. Chem. Lett.13, 1813 (2003).10.1016/S0960-894X(03)00197-5Search in Google Scholar
[99] S. Top, A. Vessières, C. Cabestaing, I. Laios, G. Leclercq, C. Provot, G. Jaouen. J. Organomet. Chem.637–639, 500 (2001).10.1016/S0022-328X(01)00953-6Search in Google Scholar
[100] C. C. A. Roux, C. Biot. Future. Med. Chem.4, 783 (2012).10.4155/fmc.12.26Search in Google Scholar PubMed
[101] B. T. Luk, L. Zhang. ACS Appl. Mater. Inter.6, 21859 (2014).10.1021/am5036225Search in Google Scholar PubMed PubMed Central
[102] S. Attar, Z. O’Brien, H. Alhaddad, M. Golden, A. Calderón-Urrea. Bioorg. Med. Chem.19, 2055 (2011).10.1016/j.bmc.2011.01.048Search in Google Scholar
[103] S. Toma. Chemicke Zvesti19, 703 (1965).Search in Google Scholar
[104] K. Shibata, I. Katsuyama, H. Murasatsu. Bull. Chem. Soc. Jpn.63, 3710 (1990).10.1246/bcsj.63.3710Search in Google Scholar
[105] R. A. Cardona, K. Hernández, L. E. Pedró, M. R. Otaño, I. Montes, A. R. Guadalupe. J. Electrochem. Soc.8, F104 (2010).10.1149/1.3439669Search in Google Scholar
[106] W. Liu, Q. Xu, B. Chen, Y. Ma. Synth. Comm.32, 171 (2002).10.1081/SCC-120001998Search in Google Scholar
[107] S.-J. Ji, Z.-L. Shen, S.-Y. Wang. Chin. Chem. Lett.14, 663 (2003).Search in Google Scholar
[108] S.-J. Ji, Z.-L. Shen, D.-G. Gu, S.-Y. Wang. J. Organomet. Chem.689, 1843 (2004).10.1016/j.jorganchem.2004.03.006Search in Google Scholar
[109] A. R. Naresh Raj, S. Sulaiman Hussaini, C. A. M. A. Huq, A. R. Suresh Babu. J. Indian. Chem. Soc.86, 1218 (2009).Search in Google Scholar
[110] A. M. Abu-Dief, I. F. Nassar, W. H. Elsayed. Appl. Organomet. Chem.30, 917 (2016).10.1002/aoc.3521Search in Google Scholar
[111] Y. Liu, L. Feng, D. Yin. J. Chem. Soc. Pakistan34, 702 (2012).Search in Google Scholar
[112] S.A. Khan, A. M. Asiri, N. S. M. Al-Ghamdi, M. E. M. Zayed, K. Sharma, H. Parveen. J. Mol. Struct.1139, 137 (2017).10.1016/j.molstruc.2017.03.044Search in Google Scholar
[113] Scifinder, version 2018; Chemical Abstracts Service: Columbus, OH, 2018; RN 58-08-2 (accessed June 26, 2018).Search in Google Scholar
[114] M. R. Otaño Vega, K. I. Rivero, I. Montes González. Acta Cryst.E70, m108 (2014).10.1107/S1600536814003912Search in Google Scholar
[115] S. M. Delgado-Rivera, G. E. Pérez-Ortiz, A. Molina-Villarino, F. Morales-Fontán, L. M. García-Santos, A. M. González-Albó, A. R. Guadalupe, I. Montes-González. Inorg. Chim. Acta.468, 245 (2017).10.1016/j.ica.2017.07.050Search in Google Scholar
[116] S. Feng, H-D. Li, Y. Gao, Y-F. Yuan. Chin. J. Appl. Chem.27, 474 (2010).Search in Google Scholar
[117] D. A. Mendez, E. Klimova, T. Klimova, L. Fernando, S. O. Hernandez, M. G. Martinez. J. Organomet. Chem.679, 10 (2003).10.1016/S0022-328X(03)00459-5Search in Google Scholar
[118] C. A. Escobar, D. Gutierrez, M. Verdugo, F. Madrid, J. C. Santos, P. Jara-Ulloa, A. Trujillo. J. Organomet. Chem.830, 1 (2017).10.1016/j.jorganchem.2016.11.025Search in Google Scholar
[119] A. D. Antuf’eva, V. E. Zhulanov, M. B. Dmitriev, I. G. Mokrushin, E. V. Shklyaeva, G. G. Abashev. Russ. J. Gen. Chem.87, 470 (2017).10.1134/S1070363217030161Search in Google Scholar
[120] H. Parveen, S. Mukhtar, A. Azam. J. Hetecycl. Chem.53, 473 (2016).10.1002/jhet.2427Search in Google Scholar
[121] M. R. Otaño Vega. MSc thesis, University of Puerto Rico at Río Piedras (2014).Search in Google Scholar
[122] T. J. Muller, J. Conradie, E. Erasmus. Polyhedron33, 257 (2012).10.1016/j.poly.2011.11.034Search in Google Scholar
[123] N. Chen, W. Wang, Q. Liao. Chem. Res. App.24, 1865 (2012).Search in Google Scholar
[124] Z-L. Gong, Y-S. Xie, B-X. Zhao, H-S. Lv, W-Y. Liu, L-W. Zheng, S. Lian. J. Fluoresc.21, 355 (2011).10.1007/s10895-010-0724-zSearch in Google Scholar PubMed
[125] A. Su, H. Li, Y. Gao, Y. Yuan. Chem. Res. App.22, 204 (2010).Search in Google Scholar
[126] M. Teng, J. Zhang, G. Huang, B. Liu, X. Li, M. Rong, T. Shen, Q. Song. J. Organomet. Chem.791, 298 (2015).10.1016/j.jorganchem.2015.05.044Search in Google Scholar
[127] Q. B. Song, X. N. Li, T. H. Shen, S. D. Yang, G. R. Qiang, X. L. Wu, Y. X. Ma. Synth. Commun.33, 3935 (2003).10.1081/SCC-120026317Search in Google Scholar
[128] Š. Toma, A. Perjéssy. Chem. Zvesti23, 343 (1969).Search in Google Scholar
[129] Q. Song, R. Lin, Z. Yang, C. Qi. Molecules10, 634 (2005).10.3390/10060634Search in Google Scholar PubMed PubMed Central
[130] H. Parveen, R. A. Suliman Alatawi, N. H. El Sayed, S. Hasan, S. Mukhtar, A. U. Khan. Arab. J. Chem.10, 1098 (2017).10.1016/j.arabjc.2015.05.002Search in Google Scholar
[131] Scifinder, version 2018; Chemical Abstracts Service: Columbus, OH, 2018; RN 58-08-2 (accessed July 6, 2018).Search in Google Scholar
[132] H. Zhao, F. Yin, L. Yu, B. Li, Z. Bian. Chin. J. Org. Chem.36, 1118 (2016).10.6023/cjoc201511045Search in Google Scholar
[133] J. J. Vazquez Bravo. Int. J. Chemtech. Res.6, 138 (2014).Search in Google Scholar
[134] A. Patti, S. Pedotti, T. Grassi, A. Idolo, M. Guido, A. De Donno. J. Organomet. Chem.716, 216 (2012).10.1016/j.jorganchem.2012.06.025Search in Google Scholar
[135] S. M. Delgado Rivera. MSc thesis, University of Puerto Rico at Río Piedras (2017).Search in Google Scholar
[136] Y. Liu, H. Xin, D. Yin, X. Yang, J. Sheng, Q. Qiao. CN Patent 106478742 A, File 29 Sep 2016, Issued 8 Mar 2017.Search in Google Scholar
[137] A. Pejović, I. Damljanović, D. Stevanović, M. Vukićevic, S. B. Novaković, G. A. Bogdanović, N. Radulović, R. D. Vukićevic. Polyhedron31, 789 (2012).10.1016/j.poly.2011.11.006Search in Google Scholar
[138] Y. Liu, L. Feng, D. Yin. J. Chem. Soc. Pakistan34, 702 (2012).Search in Google Scholar
[139] A. M. Abu-Dief, I. F. Nassar, W. H. Elsayed. Appl. Organomet. Chem.30, 917 (2016).10.1002/aoc.3521Search in Google Scholar
[140] T. H. Sum, T. J. Sum, W. R. J. D. Galloway, S. Collins, D. G. Twigg, F. Hollfelder, D. R. Spring. Molecules21, 1230, (2016).10.3390/molecules21091230Search in Google Scholar PubMed PubMed Central
[141] J. Muškinja, A. Burmudžija, Z. Ratković, B. Ranković, M. Kosanić, G. A. Bogdanović, S. B. Novaković. Med. Chem. Res.25, 1744 (2016).10.1007/s00044-016-1609-8Search in Google Scholar
[142] A. M. Asiri. Appl. Organomet. Chem.15, 907 (2001).10.1002/aoc.233Search in Google Scholar
[143] M. C. Ortega-Alfaro, A. Rosas-Sánchez, B. E. Zarate-Picazo, J. G. López-Cortés, F. Cortés-Guzmán, R. A. Toscano. Organometallics30, 4830 (2011).10.1021/om200302zSearch in Google Scholar
[144] A. Trujillo, F. Ocayo, V. Artigas, J. C. Santos, P. Jara-Ulloa, S. Kahlal, J.-Y. Saillard, M. Fuentealba, C. A. Escobar. Tetrahedron Lett.58, 437 (2017).10.1016/j.tetlet.2016.12.046Search in Google Scholar
[145] V. Janka, D. Žatko, V. Ladislav, P. Pál, P. Janka, M. Gabriela. In Vitro Cell. Dev. Biol. Animal51, 964 (2015).10.1007/s11626-015-9919-6Search in Google Scholar PubMed
[146] G. Nabi, Z. Liu. Bioorg. Med. Chem. Lett.21, 944 (2011).10.1016/j.bmcl.2010.12.051Search in Google Scholar PubMed
[147] W-y. Liu, Q-h. Xu, B-h. Chen, Y-m. Liang, Y-x. Ma, W-m. Liu. J. Organomet. Chem.637–639, 782 (2001).10.1016/S0022-328X(01)00927-5Search in Google Scholar
[148] S. Pedotti, A. Patti. J. Organomet. Chem.693, 1375 (2008).10.1016/j.jorganchem.2008.01.038Search in Google Scholar
[149] R. Ayranci, D. O. Demirkol, M. Ak, S. Timur. Sensors15, 1389 (2015).10.3390/s150101389Search in Google Scholar PubMed PubMed Central
[150] D. Li, S. Song, C. Fan. Accounts. Chem. Res.43, 631 (2010).10.1021/ar900245uSearch in Google Scholar PubMed
[151] S. Skaur, M. Kaur, B. Kaur, K. Kaur, B. Clays. Coord. Chem. Rev.343, 185 (2017).10.1016/j.ccr.2017.05.008Search in Google Scholar
[152] C. Echevarria, S. Fernandes, M. Godinho, J. Borges, P. Soares. Gels4, 54 (2018).10.3390/gels4020054Search in Google Scholar PubMed PubMed Central
[153] A. Amalraj, A. Pius, S. Gopi. J. Tradit. Complement. Med.7, 205 (2017).10.1016/j.jtcme.2016.05.005Search in Google Scholar PubMed PubMed Central
[154] S. Pisanti, A. Malfitano, E. Ciaglia, A. Lamberti, R. Ranieri, G. Cuomo, M. Abate, G. Faggiana, M. Proto, D. Fiore, C. Laezza, M. Bifulco. Pharmacol. Ther.175, 133 (2017).10.1016/j.pharmthera.2017.02.041Search in Google Scholar PubMed
[155] V. Tyagi, S. Khan, R. Shivahare, K. Srivastava, S. Gupta. Bioorg. Med. Chem. Lett.23, 291 (2013).10.1016/j.bmcl.2012.10.101Search in Google Scholar PubMed
Article note
A special collection of invited papers by recipients of the IUPAC Distinguished Women in Chemistry and Chemical Engineering Awards.
©2019 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/
