3-(Benzo[d] [1,3]dioxol-5-yl)-1-(thiophen-2-yl)prop-2-en-1-one reacted with each of thiourea and 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one to give the corresponding pyrimidine-2(1H)-thiones. Then, these compounds reacted with the appropriate hydrazonyl chlorides in dioxane in the presence of triethylamine to afford the corresponding [1,2,4]triazolo[4,3-a]pyrimidines and their related fused pyridines. Moreover, chalcone was cyclocondensed with 2-cyanothioacetamide to give pyridine-2(1H)-thione and taken as a key synthon to novel 2-(methylthio)pyridothienopyrimidin-4(3H)-one derivative. The above derivative reacted with the appropriate hydrazonyl chlorides in dioxane in the presence of triethylamine to yield the corresponding pyridothieno[3,2-d][1,2,4]triazolo[4,3-a]pyrimidines. Study of the in vitro antimicrobial activities of the newly pyrimidines were performed. Pyridothienopyrimidine 24a showed the highest inhibitory activity against all bacteria with MIC values of 3.9, 7.81, 7.81, and 15.62 μg/mL, respectively, against Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, and Streptococcus mutans, respectively, as compared to reference drugs. Molecular docking was studied to predict of the optimized conformation of pyrimidines as active ligands against the Escherichia coli alkaline phosphatase. The structures of the hybrid molecules were elucidated by IR, Mass, 1 H NMR, and 13 C NMR spectra as well as elemental analyses.
Efficient procedures are herein reported for the synthesis of novel hybrid thiazoles via a one‐pot three‐component protocol. The protocol involves the reaction of novel aldehyde, thiosemicarbazide and halogen‐containing reagents in solvent‐ and catalyst‐free conditions. The structures of the new thiazoles were elucidated by elemental analyses and spectroscopic data. The in‐vitro antibacterial screening and MurB enzyme inhibition assays were performed for the novel thiazoles. The thiazol‐4(5H)‐one derivative 6d, with p‐MeO, exhibits the best antibacterial activities with minimum inhibitory concentration values of 3.9, 3.9, 7.8, and 15.6 μg/ml against Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus mutans, and Escherichia coli, respectively, as compared to the reference antibiotic drugs. It also exhibits the highest inhibition of the MurB enzyme with an IC50 of 8.1 μM. The structure–activity relationship was studied to determine the effect of the structures of the newly prepared molecules on the strength of the antibacterial activities. Molecular docking was also performed to predict the binding modes of the new thiazoles in the active sites of the E. coli MurB enzyme.
The hydroxy macrocycles 8, 19a-c were prepared in 40-55% yields by reacting the dipotassium salts 2a-c with each of epichlorohydrin (7) and bis(chloromethyl) derivative 18. Acylation of the hydroxyl group of each of 8, 19a-c with 2-chloroacetylchloride (9) in DMF gave the corresponding esters 10, 20a,b. Reaction of the latter with different amines as well as phenoxides furnished exclusively the target lariat macrocycles 13a-c, 22a-c and 23a-c in 60-63% and 50-55% yields, respectively. Amination of two equivalents of the chloroacetyloxy derivative 10 and 2a,b with 1 equiv. of piperazine (12c) afforded the corresponding bismacrocycles 14 and 26a,b respectively, in 60-65% yields. Moreover, the novel bis(macrocycles) 27-29 were prepared in 45-50% yields, respectively, by reacting each of 20a,b with the dipotassium salts 2b, 24 and 25 respectively, in DMF. Introduction.
Both 3‐aminothieno[2,3‐b]pyridine‐2‐carboxamide derivative 4 and bis(3‐aminothieno[2,3‐b]pyridine‐2‐carboxamide) derivative 6 are prepared, starting with pyridine‐2(1H)‐thione derivative 1 incorporating 1,3‐diarylpyrazole moiety, and were taken as starting materials for the present study. Two different synthetic routes are described for the synthesis of the target materials bis(pyridothieno[1,2,3]triazin‐4‐(3H)‐one) derivative 7 and bis(pyridothienopyrimidin‐4(3H)‐one) derivatives 10 and 13. Pyridothienopyrimidin‐4(3H)‐one derivative 14 is used as a synthetic precursor for the preparation of 4‐hydrazinylpyridothieno[3,2‐d]pyrimidine derivative 18a. Compound 18a was reacted with acetylacetone to prepare the corresponding 4‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)pyrimidine derivative 19. Compound 18a was reacted with several reagents such as carbon disulfide to synthesize the corresponding derivatives 24–27 incorporating fused [1,2,4]triazole ring. Moreover, 2,4‐dihydrazinylpyridothieno[3,2‐d]pyrimidine derivative 31 was prepared starting from 3‐aminothieno[2,3‐b]pyridine‐2‐carbonitrile derivative 28. Compound 31 was reacted with each of acetylacetone and formic acid to afford the corresponding 2,4‐bis(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)pyrimidine derivative 32 and bis([1,2,4]triazolo)[4,3‐a:4′,3′‐c]pyrimidine derivative 33, respectively. Elucidation of the structures of target molecules are achieved using elemental analyses and spectral data.
Novel bis[(thiazol‐2‐yl)acetonitrile] derivatives were prepared in good yields by the cyclocondensation of bis(bromoacetyl) derivatives with two equivalents of 2‐cyanothioacetamide in dioxane at reflux. The bis[(thiazol‐2‐yl)acetonitrile] derivatives were taken as synthetic precursors for the synthesis of novel bis(aminoazolo[1,5‐a]pyrimidines), bearing thiazole moiety. The target molecules were prepared by the three component one pot reaction of bis[(thiazol‐2‐yl)acetonitrile] derivatives, dimethylformamide‐dimethylacetal and several of 3‐aminopyrazoles in pyridine under microwave irradiation at 140 °C for 2 h. Using the same protocol, novel bis(aminotriazolo[1,5‐a]pyrimidines), bis(aminopyrimido[1,2‐a]benzimidazoles) and bis(aminopyrido[1,2‐a]benzimidazoles), incorporating thiazole moieties, were prepared by using the appropriate heterocyclic amine or 2‐(1H‐benzoimidazol‐2‐yl)acetonitrile instead of 3‐aminopyrazoles. The structure of the newly prepared thiazoles was confirmed via considering their elemental analyses and spectral data.
A facile synthetic approach was adopted towards the synthesis of benzo‐fused macrocyclic lactams 2a–2g via the base‐catalyzed condensation reaction of 2,2′‐[alkanediylbis(oxy)]bis[benzaldehydes] 3a–3c with N,N′‐substituted bis[2‐cyanoacetamide] derivatives 7a–7c (Scheme 2). The latter compounds were obtained by the reaction of the appropriate diamines 6a–6c with ethyl 2‐cyanoacetate (4). Attempts to prepare the oxaaza macrocycles 2 by alternative pathways were also investigated. The novel pyrazolo‐fused macrocycles 13a and 13b were obtained in 48 and 52% yield, respectively, upon treatment of 2d and 2g with NH2NH2⋅H2O at 100° (Scheme 4).
The synthetic precursors pyridine‐2(1H)‐thiones 2a,b and bis(pyridine‐2(1H)‐thione) derivative 4, using aldehydes 1a,b incorporating 2,6‐dibromophenoxy moiety, were prepared and used to synthesize the novel target materials bis[(5‐cyanopyridin‐6‐yl)sulfanyl]butanes 5a,b, bis(2‐S‐alkylpyridines) 8a,b, and bis(3‐aminothieno[2,3‐b]pyridines) 13a–c through facile procedures. Characterization of the newly prepared compounds via elemental analyses and spectral data is established.
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