Diversity oriented syntheses of fused pyrimidines designed as potential antifolates (original) (raw)

Synthesis and antitumor activity of some nitrogen heterocycles bearing pyrimidine moiety

Journal of Heterocyclic Chemistry

Synthesis of novel pyrimidine derivatives 4-16 was accomplished by heterocyclization of polarized system, for example, Chalcone. Claisen-Schmidt condensation of 2-acetyl naphthalene with 4-(N, N-dimethylaminoben zaldehyde) afforded chalcone 3, which was utilized for synthesis various pyrimidine derivatives by treatment with urea, thiourea, and guandine hydrochloride in ethanolic sodium hydroxide solution. The reactivity of the synthesized pyrimidine derivatives towards different nucleophilic and electrophilic reagent were examined. The constructions of the newly synthesized pyrimidine derivatives were elucidated from their spectral and elemental analysis. All the synthesized compounds were tested in vitro for their anticancer activities against HePG-2 and MCF-7 cell lines. Some of them posses a wide range of pharmacological activity. Finally, a molecular docking study was conducted to reveal the probable interaction with the dihydrofolate reductase (DHFR) active site. 1 | INTRODUCTION Chalcones have a considerable interest to medicinal chemists and are widely used as antimicrobial, [1-3] anticancer, [4,5] antitumor, [6] antitubercular, [7] antioxidant, antidiabetic, [8,9] anti-inflammatory, [10] antimalarial, [11] antileishmanial, [12] and antiviral activity. [13] They are well known intermediates for synthesizing various heterocyclic compounds. Cyclization of chalcones, leading to thiazines, pyrimidines, pyrazoline has been a developing field within the realm of heterocyclic chemistry for the past several years because of their ready accessibility and the broad spectrum of biological activity of the products as antibacterial, antifungal, antiprotozoal, antiinflammatory substances. A survey of literature in the recent past reveals that pyrimidine heterocyclic core has a capital value in pharmacologically active skeletons since it contains the base for uracil, thiamine, and cytosine nitrogen bases, which are the building blocks of the nucleic acids. [14,15]

Design, Synthesis, and Molecular Modeling of Novel Pyrido[2,3-d]pyrimidine Analogues As Antifolates; Application of Buchwald–Hartwig Aminations of Heterocycles

Journal of Medicinal Chemistry, 2013

Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg) and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogs. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR.

Synthesis, Cytostatic and Antibacterial Evaluations of Novel 1,2,3-Triazolyl-tagged Pyrimidine and Furo[2,3-d]pyrimidine Derivatives

Croatica Chemica Acta

C-5 alkynylated and N-1 alkylated pyrimidine derivatives were synthesized by N-alkylation reaction of 5-iodouracil in the presence of NaH, as a base, followed by Pd-catalyzed Sonogashira cross-coupling reaction of N-alkyl-5-iodouracil derivatives (1 and 2) with corresponding terminal alkynes. Intramolecular in situ O-heteroannulation ring closure of N-1-alkyl-C-5-alkynylpyrimidine derivatives (3 and 5) generated novel 6-substituted furo[2,3-d]pyrimidine derivatives (7 and 8). 1,4-Disubstituted 1,2,3-triazole tethered 5-alkynylpyrimidines (14-19) and 6-substituted furo[2,3-d]pyrimidines (20-22) were successfully prepared by the copper(I)-catalyzed click reaction of 5-iodo-N-1-propargylpyrimidine (2) using microwave irradiation, followed by Sonogashira cross-coupling reaction with corresponding terminal alkynes. In vitro antiproliferative activity of prepared compounds evaluated on human cancer cell lines cervix adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), chronic myeloid leukemia in blast crisis (K562), Burkitt lymphoma (Raji) revealed that pyrimidine (19) and furo[2,3-d]pyrimidine (22) derivatives with 3,5-difluorophenyl at pyrimidine and furo[2,3-d]pyrimidine as well as p-(trifluoromethyl)phenyl at 1,2,3-triazole exhibited marked and selective inhibitory effects on the growth of K562 and Raji tumor cells. Antibacterial evaluations showed that pyrimidine derivative 14 substituted with p-tolylethynyl at C-5 of pyrimidine and benzyl at 1,2,3-triazole moiety was the most active of all evaluated compounds on the Gram positive bacterial strains Enterococcus faecalis. Further structure optimization of compounds 14, 19 and 22 is foreseen in order to obtain lead structural analogs with efficient and selective antitumoral and antibacterial activities.

Synthesis and biological Evaluation of Some Abbreviated New pyrimidine derivatives

International Journal of Scientific Research in Science and Technology, 2019

A cogent synthesis of completely new compound series of by 6-(3,5-bis(trifluoromethyl)phenyl)-4-(4-chlorophenyl)-3,4-dihydro pyrimidine-2(1H)-one (Biginelli reaction) was achieved by continue heating of (E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(substituted phenyl)prop-2-en-1-one and urea for 5 hours with 40% KOH and ethyl alcohol. (E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(substituted phenyl)prop-2-en-1-one is produced by Claisen-Schmidt Condensation. In this condensation 1-(3,5-bis(trifluoromethyl)phenyl)ethanone and different aldehyde are mixed. All the novel compound series were characterized by infrared and 1H nuclear magnetic resonance and mass spectroscopic techniques and by elemental analyses. The newly synthesized compounds were evaluated for their antibacterial and antifungal activity

Design, synthesis of new pyrimidine derivatives as anticancer and antimicrobial agents

2017

A new series of 6-aryl-5-cyano thiouracil derivatives were synthesized. Cyanouracil 1 was condensed with monochloroacetic acid and different aldehydes to give thiazolopyrimidine 2. On the other hand, treatment of cyanouracil 1 with 2-chloro-N-substituted-phenylac etamide afforded 4. Hydrazinolysis of 6 afforded the hydrazino derivatives 7 which upon reaction with different electrophilic reagents such as acetic anhydride, benzoyl chloride, and carbon disulfide yielded pyrimidine derivatives 8–15. Some of the new derivatives were explored for their antimicrobial activities. Compounds 7 and 9 have a promising activity, relatively equipotent to the reference drug. All of the new synthesized compounds were tested in vitro for their antiproliferative activities against HePG-2 and MCF-7 cell lines. Compounds 7, 9, and 2d displayed potent growth inhibitory effect toward the two cell lines more than the standard drug 5-FU. Furthermore, a docking study of the most active compounds was performed with thymidylate synthase enzyme.

Proficient synthesis of bioactive annulated pyrimidine derivatives: A review

Journal of Taibah University for Science

Syntheses of bioactive annulated pyrimidine derivatives are the most significant tasks in N-heterocyclic chemistry because these compounds have proved to be very attractive and useful for the design of new molecular frameworks of potential drugs with varying pharmacological activities. This review paper summarizes the one-pot multicomponent synthesis of annulated nitrogen-and oxygencontaining heterocycles, such as pyrano[2,3-d]pyrimidines, pyrido[2,3-d]pyrimidines and pyrido[2,3-d;5-6-d]dipyrimidines. The synthetic procedure is based on the chemistry of the domino Knoevenagel-Michael addition mechanism.

Synthesis and anticancer activity of some fused pyrimidines and related heterocycles

On account of the reported anticancer of pyrimidine and condensed pyrimidine, a new pyrimido [3,2-b]-1,2,4,5-tetrazine 3 a,b , 5 c,d , 6, 9, pyrimido [3,2-b]-1,2,4-triazine 10, 11, pyrimido [3,2-b]-1,2,4-triazole 12 and pyrimidine derivatives 1,2 a,b , 4 c,d , 8, 13, 14, 15 and 16 were synthesized through different chemical reactions. Structures of all synthesized compounds were supported by spectral and elemental analyses. The obtained compounds were evaluated for their in vitro antitumor activity against human liver cancer cell line (HEPG2).