Synthesis of New Functionalised Derivatives of [1,2,4]triazolo[4,3-a]Pyrimidine and Pyrimido[2,1-b][1,3,5]Thiadiazine as Aromatase Inhibitors

Abstract

Thiadiazines are class of heterocyclic compounds that posses antimicrobial, 1-7 tuberculostatic, 8 antiprotozoan, 9 antihelmintic, 2 antifibrinolytic 7 and anticancer 10 activities. Fused derivatives of 1,3,5-thiadiazine are most suitably synthesised by a Mannich-type condensation of mercaptoazoles with formaldehyde and primary amines. 11,12 The [1,2,4]-triazolopyrimidines are pharmacological scaffolds displaying a wide range of biological activities such as antitumour, 13 human A3 adenosine receptor, 14 antimicrobial, 15,16 antiallergy 17 and 5a-reductase inhibitors. 18 In continuation of our efforts [19][20][21][22][23][24] to synthesise new heterocyclic compounds that may have potent biological activities, we decided to synthesise new triazolopyrimidines and pyrimidothiadiazines and to investigate their activity as aromatase inhibitors compared with the drug letrozole. Results and discussionThiobarbituric acid 1 was prepared as previously reported. 25 Reaction of thione 1 with different primary aromatic amines, aqueous formaldehyde solution and catalytic amounts of concentrated HCl in ethanol at room temperature, afforded in each case, only one product, as examined by TLC, which was identified as the respective pyrimidothiadiazinones 3a-g through the di-Mannich reaction (Scheme 1). The structures of compounds 3a-g were confirmed by spectroscopic data and elemental analyses. For instance, the IR spectra of compounds 3a-g were devoid of absorption bands at 3400-3100 cm -1 characteristic for 2NH functions. The 1 H NMR spectrum of compound 3a, taken as a typical example, showed two peaks for the methylene protons of the 1,3,5-thiadiazine rings at δ 5.44 and 5.96, two singlets attributed to the methine protons at 6.74 and 6.76 ppm, in addition to an aromatic multiplet in the region 6.94-7.32 ppm. The mass spectrum of compound 3a revealed the molecular ion peak at m/z 261.The thione 1 reacts with the hydrazonoyl chlorides 4a-k dioxane in the presence of a catalytic amount of triethylamine while stirring at room temperature. In all cases, hydrogen sulfide was evolved during the course of the reaction and so the stirring of the reaction mixture was continued until hydrogen sulfide ceased to evolve. Work-up of the reaction mixture afforded, in each case, one isolable product as evidenced by TLC analysis of the crude product. The structures of the products were assigned on the basis of their elemental analyses and IR and 1 H NMR spectra which showed all the expected signals (see Experimental).The formation of compounds 8 from 1 and 4 could be accounted for by the hydrazonoylation of 1 to give the thiohydrazonate esters 5, which is followed by Smiles type rearrangement 26 to afford the respective thiohydrazides 6. This latter compound 6, in turn, underwent cyclisation to give 8 as the end products (Scheme 2). It seems likely that both intermediates 5 and 6 are consumed, under the employed reaction conditions, as soon as they are formed since all attempts to isolate them failed.Thione 1 (2 equiv.) were allowed to react wi...

Aromatase Inhibitors as a Promising Direction for the Search for New Anticancer Drugs

“…The most active compound 67 ( Figure 13 ) in this series showed an IC 50 value of 1.1 nM. Antitumor activity tests against cell lines were not performed [ 57 ].…”

Synthesis, Antitumor Evaluation and Molecular Docking of New Morpholine Based Heterocycles

“…In recent years, interest in the chemistry of hydrazonoyl halides has been renewed because of the development of novel synthetic routes and their use as synthons for compounds that find many applications [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. The literature reveals that the presence of a morpholine ring on a heterocyclic system contributes to enhanced pharmacological activities in many cases [ 11 , 12 , 13 , 14 , 15 , 16 ].…”

Synthesis of Some Novel 1,4‐Phenylene‐bis‐thiazolyl Derivatives and Their Anti‐hypertensive α‐blocking Activity Screening

“…In the last two decades we have been involved in a program aiming to the synthesis of functionally substituted heterocyclic compounds from cheap laboratory available starting materials to be screened as biodegradable agrochemicals [1][2][3]. Within the frame of this program we have recently reported many syntheses of several novel bisheterocyclic compounds [4][5][6].…”