Derivatives of 1,2,4-Triazole-3,4-Disubstituted Based on Aminoacids with Potential Biological Activity

In order to obtain new substances with potential biological activity dipeptide derivatives from p-aminobenzoyl-phenylglycine and p-aminobenzoyl-phenylalanine were grafted on 1,2,4-triazolic heterocycle. The new synthesized compounds belong to the group of antimetabolites, group used in medicine for treating malignant tumors. Also, it is possible to study the correlation between chemical structure and biological activity of the new compounds.


1.Introduction
The malignant tumours are considered serious health problems today. The current trend in chemotherapy of malignant tumours is characterized by using the treatments with the compounds that manifests as antimetabolites. Among all the current therapeutic methods, chemotherapy remains an important option for cancer treatment: inhibition of the characteristic proliferation pathways of cancer cells constitutes an effective strategy to fight this pathology.
In order to obtain derivatives with reduced toxicity and high therapeutic action, a series of syntheses were performed by replacing the hydrogen of the amino group in the molecule of the N-(paminobenzoyl)-D,L-phenylglycine and N-(p-aminobenzoyl)-L-phenylalanine with the 5-mercapto-1,2,4-triazole-3,4-disubstituted heterocyclic system. D,L-phenylglycine and L-phenylalanine derivatives were synthesized by V. Sunel and collaborators, compounds which have been shown to be active against various pathogens [48,49].
The study of the mutual influence of the three components which are present in the same molecule as well as their contribution to the global biological activity of the substance it is interesting.
The aim of this research was to establish some physico-chemical properties of the synthesized 1,2,4-triazole-3,4-disubstituted based on aminoacids derivatives having in view their potential biological activity.
The triazole derivatives were obtained by cyclization in basic medium of acyl-thiosemicarbazides, prepared in turn by condensation of isothiocyanates with 5-nitroindazole-1-yl-acetic acid hydrazide [27].
I, IV R = -C6H5; II, V R = -C6H4-CH3 (p); III, VI R = -C6H4-OCH3 (p); Due to the presence in their molecule of thioamide group , 5-thio-1,2,4-triazoles-3,4disubstitution presents the phenomenon of double reactivity, in the sense that in depending on the nature of the reactant and the working conditions, it reacts as if it had either the thionic structure IV-VI (A) or the thiolic structure IV-VI (B). This property explains the existence of the reaction center at the sulphur atom at position 5 of the triazolic heterocycle.
The mercapto triazole in SH form reacts with the ethyl ester of bromoacetic acid, in basic medium forming S-derivatives VII-IX (Scheme 1) asymmetric vibrations of NO2 group appear in all IR spectra. The compounds XII and XV still have a band at 1107 cm -1 , respectively at 1109 cm -1 attributed to the methoxy group.
The absorption band of the S-CH2 group, at 746-790 cm -1 , an intense band at 815-897 cm -1 specific for the p-disubstituted benzene nucleus, as well as a broadband specific to the -COOH group in the domain 3242-3286 cm -1 were identified in IR spectra of all studied compounds. Signals at 2.87-3.30 ppm attributed to the protons of the CH2 group next to the CO bond to NH group from N-(p-aminobenzoyl)-D,L-phenylglicine and N-(p-aminobenzoyl)-L-phenylalanine respectively and at 4.5-5.97 ppm to the proton of the CH group appear in NMR spectra of all compounds X-XV.
In NMR spectra of compounds XI and XIV, the protons corresponding to the methyl group appear as a single at 2.11-2.43 ppm, while, the signal recorded in the range 3.90-3.94 ppm is assigned to the protons of the OCH3 group. The NH amide groups are identified by peaks that appear as a single at 7.80-8.06 ppm and a doublet at 8.15-8.87 ppm. The proton of the carboxylic group appears in domain 12.20-12.95 ppm which shows that the graft reaction of dipeptides on the triazole nucleus took place.
The structures X-XV were supposed to a quantum chemical analysis with Spartan 14 and some electro-optical parameters were computed after the geometry optimization [51]. Some dependences can be established for these compounds. There is a tendency ( Figure 1) to increase the electric dipole moment in the ground state of the molecules with the increase in the modulus of the formation energy in the case of compounds X-XII and a tendency to slowly decrease in the modulus of the molecular energy in the case of compounds XIII -XV. The two groups of substances have similar chemical structures, excepting the atomic group -NH added in the second group of structures.
For all studied molecules the ground state polarizability increases with the modulus of the computed molecular energy. The increase in the electric dipole moment of the molecules from the group X -XII is induced by the decrease in the electronic charge near the first oxygen atom of NO2 atomic group. Contrarily, the same decrease determines the decrease in the dipole moment for the molecules belonging to the second group XIII -XV.
The electronic charges localized near the second oxygen atom of NO2 atomic group does not influence significantly the molecular dipole moment for the studied molecules. https://doi.org /10.37358/Rev. Chim.1949 Rev. Chim., 71 (5)  The electronic charge localized near nitrogen atom of -NH group influences the values of the electric dipole moment in the ground state of the studied molecules, by increasing it in the case of X -XII group and decreasing it in the case of the group XIII -XV.

3-[(5'-nitro-1H-indazole-1'-yl)-methyl]-4-aryl-1,2,4-triazole-5-thioacetic esters (VII-IX), General procedure:
In a suspension of 0.01 mol of triazole in 150 mL of anhydrous ethanol was added 0.02 mol of sodium ethoxide and stirred for 10 min. 0.01 mol of monobromoacetic acid ethyl ester was added, while stirring for 4 h at 65-70°C. In the end of the reaction 200 mL of anhydrous benzene are added and stirring is continued, for 30 min. The separated benzene layer is washed with a lot of distilled water in the separation funnel and then dried over anhydrous sodium sulphate. The benzene was distilled off under reduced pressure and the crude product precipitated out of the residue with anhydrous ethyl ether as crystals.
The final product is purified by recrystallization from ethyl alcohol.
From the reaction mixture a compound is precipitated with water after the cooling, a compound which, after purification by repeated recrystallization from acetone and anhydrous ethyl alcohol appears as white crystals.