TECHNICAL FIELD

[001] The present invention is directed to the field of chemical synthesis, mainly tp the technical field of coordination compounds obtained from dithiocarbamates derived from para-phenyldiamine and metal ions and the obtaining process thereof useful to combat Escherichia coli and Staphylococcus aureus and a wide application as antifungals, removers of heavy metals in contaminated water sources, antimicrobial and anticancer agents.

STATE OF ART

[002] Worldwide, there is a very high mortality rate in the population due to diseases caused by bacteria, especially those diseases caused by bacteria such as Escherichia coli and Straphylococcus aureus, added to the fact that there is currently resistance of these bacteria to commonly used antibiotics, which limits the effectiveness of antibiotic treatment and can cause a large number of diseases, causing a risk to a large number of people and problems for public health.

[003] In the state of the art related to patents it is known, for example, document CN110683975 which discloses organic sulfur compounds, wherein dialkylamino dithiocarbamate alkyl ester plays a very important role because they have broad biological characteristics and pharmacological activity and can be used as a myocardial imaging agent. It is known that dialkylamino dithiocarbamate alkyl ester and derivatives thereof can be taken as HIV-1 NCp7 inhibitors, antiviral agents and non-flavonoid TRPV1 antagonists. The invention further provides a method for efficiently synthesizing amino dialkyl dithiocarbamate alkyl ester, under Cui catalysis, via a chiral quaternary ammonium salt and an aminodialkyl dithioformylate for C-S cross-coupling, and the dialkylamino dithiocarbamate alkyl ester is prepared.

[004] Also known is CN112661685 which reports a process method for the one-step synthesis of dithiocarbamate using a microflow field technology. The method consists of the steps of pumping alkylamine, carbon disulfide, zinc chloride and alkaline liquor into a reactor according to a given flow rate by using a microflow field reactor, maintaining a given temperature and retention time, discharging, resting and separating the liquid, washing with water and distillation at reduced pressure to obtain the product. Depending on the method, the operation steps are optimized, the reaction time is significantly shortened and a continuous production of the product is realized.

[005] On the other hand, it is known from document CN110483355 that describes a synthetic method of zinc dialkyl dithiocarbamate. The preparation method comprises the steps of adding 1 part by weight equivalent of zinc oxide powder and 2.0-2.5 parts by weight equivalent of dialkylamine in 60-100 parts by weight of a solvent under mechanical stirring and then slowly, dropwise adding 2.0-2.5 parts by weight equivalent of carbon disulfide; and stirring the mixture for 1-12 hours, heating the mixture to 50-95°C, removing the water generated in the reaction process by distillation under reduced pressure and finally filtering the mixture to obtain the required product.

[006] In turn, CN103804258 discloses a dithiocarbamate synthesis process, which comprises the steps: (a) adding an amount of carbon disulfide, alkali liquid and carbamide in a reaction vessel; (b) stirring continuously, after uniform mixing, controlling the temperature and adding carbon disulfide dropwise; (c) controlling the temperature and stirring; (d) heating the solution; (e) once the reaction is finished, stirring, cooling to crystallization and filtering; (f) performing vacuum drying to obtain dithiocarbamate. Dithiocarbamate is synthesized using carbon disulfide and carbamide according to the process parameters; the synthesis method is simple in synthesis step, high synthesis efficiency and low synthesis cost. In addition, the synthesized dithiocarbamate is effective and has a wide range of applications.

[007] Additionally, there is known document CN113444114 which relates to the application of a dibenzyl copper dithiocarbamate drug in the treatment of breast cancer, and a method of preparing the drug comprising the steps: 1) synthesizing sodium dibenzyldithiocarbamate: stirring 11.8 g of dibenzylcylamine and 150 ml of acetonitrile in an ice water bath, adding 6.96 g of carbon disulfide and sodium hydroxide in a reaction vessel, stirring to react for 16 hours, then filtration under vacuum, evaporation with rotavap on the filtrate to obtain a product, which is washed with diethyl ether and dried to obtain 13.04 g of the product and recrystallization with acetonitrile to obtain sodium dibenzyl dithiocarbamate with a mass of 11.1 g. On the basis of an anticancer structure of disulfiram, a new drug copper dibenzyldithiocarbamate, which improves lipid solubility and has a good inhibition effect on drug-resistant breast cancer, is synthesized again.

[008] In the scientific literature we know of the article entitled “Fungicidal and bactericidal activity of metal diethyldithiocarbamate fungicides” by H.S. Rathore et al published in Journal of Thermal Analysis and Calorimetry, 2008 which reports the synthesis of copper diethyldithiocarbamate, cadmium diethyldithiocarbamate, lead diethyldithiocarbamate, nickel diethyldithiocarbamate and zinc diethyldithiocarbamate. They have been characterized by TG, DTA, IR and X-ray spectroscopy. The thermal conversion of the compounds is 54.36 to 88 % at 1000 °C. Their solubility in sodium hydroxide, mineral acids, organic solvents, distilled water and salt solution has been measured. The fungicidal activity of dithiocarbamates has been tested by the well diffusion method using five fungal species. Their activity has also been tested by the broth dilution method using six bacterial species. The minimum inhibitory (bactericidal) concentration is 6.25-25.00 pg/mL.

[009] Also known is the article entitled “Synthesis, characterization, thermal, antimicrobial and antioxidant studies of some transition metal dithiocarbamates” by Damian C. Onwudiwe et al. published in Research on Chemical intermediates 2017 which reports the synthesis of metal dithiocarbamate complexes of Co(ll), Cu(ll), Mn(ll), Cr(lll) and Pd(ll) using ethyl N-N-phenyldithiocarbamate (NaL) sodium salt. The complexes were characterized by elemental analysis, FTIR and UV-vis spectroscopic techniques, magnetic moment, molar conductance and thermal analysis (TGA and DSC). Infrared spectra indicated the coordination of dithiocarbamate through the two sulfur atoms in a symmetrical bidentate fashion. The thermal behavior of these complexes showed that the hydrated complexes lost water molecules in the first step, followed by the decomposition of the ligand molecules in the final steps. The antimicrobial potentials of the complexes were evaluated against selected bacterial strains (Escherichia coli, Pseudomonas aureginosa, Salmonella typhi and Staphylococcus aureus) and fungal organisms (Aspergillus flavus and Fasiparium oxysporium).

[010] Finally, we are aware of the article entitled “Synthesis, characterization and antibacterial studies of nickel (II) mixed ligand complexes of dithiocarbamate ligands with Schiff base” by Itohowo G. Asuquo et al published in Elixir Appli. Chem 2014 which reports the characterization of mixed nickel(ll) chelates of Schiff base derived from salicylaldehyde and aniline with various dithiocarbamate ligands by metal analysis, microbial activity, solubility and infrared spectra measurements. The electronic spectra reveal that the nickel complexes are typical of square plane as evidenced by the presence of two d-d absorption bands. The synthesized compounds showed moderate to high antibacterial activity against the test bacteria and may be effective as antibiotics.

[011] In this sense, there is a need to provide coordination compounds and their process of obtaining thiocarbamates derived from para-phenyldiamine with Ni ²⁺ , Cu ²⁺ and Mn ²⁺ metal ions that have application as antifungals, as removers of heavy metals in water sources, antimicrobial and anticancer agents and given the bactericidal activity of thiocarbamate ligands and their metal centers provide a synergy between these properties through the stabilization of coordination compounds.

SUMMARY

[012] The present invention is directed to coordination compounds obtained from thiocarbamates derived from para-phenyldiamine and metal ions and their obtaining process to combat Escherichia coli and Staphylococcus aureus and a wide application as antifungals, heavy metal removers in contaminated water sources, antimicrobial and anticancer agents.

DESCRIPTION OF THE FIGURES

[013] Figure 1 shows a ¹ H Nuclear Magnetic Resonance ( ¹ H NMR) spectrum of amine 4, wherein the hydrogens present in the molecule are observed.

[014] Figure 2 shows the ¹³ Carbon Nuclear Magnetic Resonance (- ¹³ C NMR) spectrum of amine 4, wherein the carbons present in the molecule are observed.

[015] Figure 3 shows the infrared spectrum of amine 4 wherein the different functional groups present in the molecule are observed.

[016] Figure 4 shows the infrared spectrum of the copper coordination compound (5), wherein the vibrations of the bonds that are present in the molecule can be observed. [017] Figure 5 shows the electronic spectrum of the copper coordination compound

(5), wherein the most important electronic transitions exhibited by the molecule can be observed.

[018] Figure 6 shows the infrared spectrum of the nickel coordination compound (6), wherein the vibrations of the bonds that are present in the molecule can be observed.

[019] Figure 7 shows the electronic spectrum of the nickel coordination compound

(6), wherein the most important electronic transitions presented by the molecule can be observed.

[020] Figure 8 shows the infrared spectrum of the manganese coordination compound (7), wherein the vibrations of the bonds present in the molecule can be observed.

[021] Figure 9 shows the electronic spectrum of the manganese coordination compound (7), wherein the most important electronic transitions exhibited by the molecule can be observed.

DETAILED DESCRIPTION OF THE INVENTION

[022] In a first aspect, the present invention refers to metal-coordinated aromatic amine derivatives with applications as bactericidal materials, wherein the general formula (I) of said compounds has the following structure: wherein M is a metal selected from the group consisting of copper, nickel and manganese.

[023] In a second aspect, the present invention relates to a procedure for the preparation of the compounds of formula (I) by a series of steps: Step 1

Step 3

[024] In this regard, the process of obtaining metal-coordinated aromatic amine derivatives according to the present invention comprises the following steps: a) Contacting a diamine of formula (1) with benzaldehyde of formula (2) in an anhydrous solvent in a microwave oven at a power of 300 W, for a time between 10 and 30 minutes at a temperature between 50°C and 70°C; b) Adding sodium borohydride (NaBH ₄ ) at room temperature and continue the reaction in a microwave oven for between 30 minutes and 60 minutes at the same power as in the first step; and c) Obtaining the coordination compound of formula (I) in situ by dissolving N',N'- dibenzylbenzene-1 ,4-diamine of formula (4) in methanol (MeOH), addition of ammonium hydroxide (NH4OH), dropwise addition of carbon disulfide while stirring at room temperature and addition of the respective salts: CuCI ₂ .2H ₂ O, NiCl2.6H ₂ O, and MnCI ₂ .4H ₂ O.

[025] According to the production process in accordance with the present invention, the first step (a) is the reaction of the p-diamine of formula (1 ) with benzaldehyde of formula (2) in an anhydrous solvent, such as dry methanol, wherein the reaction is carried out in a microwave for a time between 10 and 30 minutes, more preferably 20 minutes, a temperature between 50°C and 70°C more preferably at 60°C and a power of 300 W until the corresponding imine of formula (3) is obtained.

[026] In the second step (b), to the imine of formula (3) is added sodium borohydride (NaBH ₄ ) at room temperature (18°C to 25°C) continuing the reaction in a microwave for a given time, for example, between 30 minutes and 60 minutes, more preferably 40 minutes and at the same power as in the first step. After the time in the microwave, the reaction mixture is subjected to evaporation at a rotavap until dryness and subsequently, a saturated aqueous solution of sodium chloride is added and extraction with dichloromethane (DCM) is performed in triplicate, wherein the organic phases are collected and again subjected to evaporation at a rotary evaporator until the volume is reduced to between 5% and 10% of the initial volume of the collected organic phases. Then distilled water is added and with constant agitation a hydrochloric acid solution is added until a pH between 1 and 3 is obtained. After the addition of the acid, dichloromethane (DCM) is added in order to perform a new extraction which is also done in triplicate and the aqueous phase is collected, wherein a white solid is formed and subjected to filtration and washed with dichloromethane (DMC). The washed solid is dissolved in water and saturated aqueous solution of sodium carbonate (Na ₂ COs) is added until the solution is alkalinized. The extraction is performed again with DCM and the organic phases are collected and evaporated to dryness. In this way the amine of formula (4) is obtained as a gray solid with a yield of 62%. [027] In the third step (c) to obtain the coordination compounds of formula (I) according to the present invention, the reaction of the coordination compound is carried out In situ starting from the amine of formula (4), without isolation of dithiocarbamate (DTC) in a ligand:metal ratio of 1.00:1.20. Initially N',N'-dibenzylbenzene-1 ,4-diamine (4) is dissolved in methanol (MeOH) and ammonium hydroxide (NH4OH) is added with constant stirring for 12 hours. Subsequently, carbon disulfide is added dropwise with stirring at room temperature for a period of 2 hours, the reaction is monitored by plate chromatography until the disappearance of the amine. After this time the respective salts are added:

[028] In order to obtain the copper compound, the reaction is left stirring at room temperature for 2 hours and for the nickel and manganese compounds the reaction is left stirring at reflux for a period of 12 hours. After these times crystals are obtained which are filtered and washed with methanol to obtain the copper coordination compound of formula (5) as a dark brown solid; the nickel coordination compound of formula (6) as a black solid and finally the manganese compound of formula (7) was obtained as a dark green solid.

EXAMPLE OF THE BEST WAY TO CARRY OUT THE INVENTION

Synthesis of N',N'-dibenzylbenzene-1 ,4-diamine (4)

[029] 1 ,4-phenyldiamine (1 ) (300 mg; 2.78 mmol) and benzaldehyde (2) (2.36 g; 22.24 mmol) dissolved in dry methanol (15 ml) were added to a microwave vial. The reaction mixture was microwaved for 20 min, at 60°C and a power of 300 W, thus obtaining the corresponding imine (3), performing TLC monitoring. The reaction mixture was brought to room temperature and NaBH ₄ (1.05 g; 27.8 mmol) was slowly added and the vial was microwaved again for 30 min at 25°C and a power of 300 W.

[030] After this time the reaction mixture was evaporated by rotavap to dryness, then 15 ml of a saturated aqueous solution of sodium chloride was added and the extraction was carried out with 20 ml of dichloromethane (DCM) in triplicate. The organic phase was collected and again evaporated by rotary evaporator until the volume was reduced to approximately 5 ml. It was added 20 ml of distilled water and in constant agitation a solution to 20% of hydrochloric acid was added until acidifying the solution. Subsequently, 20 ml of DCM was added to perform again the extraction in triplicate and the aqueous phase was collected. When a white solid was formed, it was filtered and washed with 10 mL of DCM in triplicate; this solid was dissolved in 20 mL of water and a saturated solution of sodium carbonate was added until alkalinizing the solution. Again, an extraction was made with 20 mL of DCM and the organic phase was collected, evaporated to dryness and the amine of formula (4) was obtained as a gray solid in 62% yield.

Spectroscopic information

[031] Amine of formula (4) N',N'-dibenzylbenzene-1 ,4-diamine. ¹ H NMR (300MHz, CDCI ₃ ) d/ppm 7.24-7.37 (m, 10H, Ar-H), 6.57 (s, 4H, Ar-H), 4.26 (s, 4H, CH ₂ -Ar), 3.67 (s, 4H, NH ₂ ). ¹³ C RMN (300MHZ, CDCI3) d/ppm 140.9, 140.1 , 128.7, 127.8, 127.2, 114,87. IR [Pastilla de KBr, u(cm’ ¹ )] 3405-3339 (uN-H), 3020 (uC=C-H), 2909 (uC- C-H), 1507 (uC=C), 1239 ((uC-N).

Synthesis of the coordination compounds of formulas 5, 6 and 7

[032] The reaction of the coordination compound was carried out In situ starting from the amine of formula (4), without isolation of the DTC at a binder:metal ratio of 1.00:1.20. Initially N',N'-dibenzylbenzene-1 ,4-diamine of formula (4) (100 mg; 0.346 mmol) was dissolved in 15 mL of MeOH and ammonium hydroxide NH4OH) (39.6 mg; 1.39 mmol) was added under constant stirring for 12 hours. Subsequently carbon disulfide (CS2) (158.4 mg; 2.08 mmol) was added dropwise (158.4 mg; 2.08 mmol) under constant stirring at room temperature for a period of two hours, the reaction was followed by plate chromatography until the disappearance of the amine. After this time the respective salts CuCl2.2H ₂ O (71.0 mg; 0.416 mmol), NiCl2.6H ₂ O (54.0 mg; 0.416 mmol) and MnCI ₂ .4H ₂ O (80.0 mg; 0.416 mmol) were added.

[033] For the copper compound the reaction was left stirring at room temperature for 2 hours and for the nickel and manganese compounds the reaction was left stirring at reflux for a period of 12 hours. After these times crystals were obtained which were filtered and washed with methanol to obtain the copper coordination compound of formula (5) as a dark brown solid; the nickel coordination compound of formula (6) as a black solid and finally the manganese compound of formula (7) was obtained as a dark green solid. Spectroscopic information

[034] Coordination compound 5. IR [KBr pellet, u(cm ^-1 )] 3150 (uAr-H), 1505 (uC=C), 1416 (uC==N), 1079 (uC-S), 686 (uS-Cu). UV electron spectroscopy [CH2CI2 1x10“ ³ M, l(nm)] 294 (Transitions n— >TT* and absorption intraligand and aromatic rings),

351 (Ligand^Metal charge transfer), 517 (Transition d^d Metal).

[035] Coordination compound 6. IR [KBr pellet, u(cm ^-1 )] 3161 (uAr-H), 1517 (uC=C), 1396 (uC==N), 1086 and 995 (uC-S), 694 (uS-Ni). UV electron spectroscopy [CH2CI2 1x10 ^-3 M, l(nm)] 295 (Transitions n— >TT* absorption intraligand and aromatic rings), 336 (Ligand^Metal charge transfer), 420 (Transition d^d Metal).

[036] Coordination compound 7. IR [KBr pellet, u(cm ^-1 )] 3198 (uAr-H), 1512 (uC=C), 1409 (uC==N), 1175 and 1086 (uC-S), 686 (uS-Mn). UV electron spectroscopy [CH2CI2 1x10 ^-3 M l(nm)] 300 (Transitions n— >TT* and intraligand and aromatic ring absorption), 361 (Ligand^Metal charge transfer). [037] Finally, the person skilled in the art will understand that the process of the present invention may also be carried out with aromatic diamines in the ortho and meta positions, wherein the coordination compounds are characterized by IR and ultraviolet visible spectroscopy and the starting amine is characterized by NMR and IR.