Pyrimidines 6a Research Articles

Synthesis, docking, machine learning and antiproliferative activity of the 6-ferrocene/heterocycle-2-aminopyrimidine and 5-ferrocene-1H-Pyrazole derivatives obtained by microwave-assisted Atwal reaction as potential anticancer agents

A simple and fast methodology under microwave irradiation for the synthesis of 2-aminopyrimidine and pyrazole derivatives using Atwal reaction is reported. After the optimization of the reaction conditions, eight 2-aminolpyrimidines containing ferrocene and heterocycles and three ferrocene pyrazoles were synthesized from the respective chalcones in good yields. Eight compounds had their structure determined by X-ray diffraction. The molecular hybrid 6a-h and 9a-c were tested on four cancer cell lines - HCT116, PC3, HL60 and SNB19 - where four pyrimidine 6a, 6f-h and one pyrazole 9c derivatives show promising antiproliferative activity. In addition, docking simulation and machine learning methods were carried out to explain the biological activity achieved by the synthetized compounds.

Discovery of new thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives as orally active phosphoinositide 3-kinase inhibitors

As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure–activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.

Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases.

A series of mono-pyrrolo[2,3-d]pyrimidines 4a–4k, unsymmetrical bis-purine isosteres 5a–5e and symmetrical bis-pyrrolo[2,3-d]pyrimidines 6a and 6b connected via di(1,2,3-triazolyl)phenyl linker were synthesized by click chemistry. Whereas mono- 4g and bis-pseudopurine 5e showed selective inhibitory activities on cervical carcinoma (HeLa) cells, bis-pyrrolo[2,3-d]pyrimidine 6b exhibited potent and selective anti-proliferative effect in the nanomolar range on pancreatic carcinoma (CFPAC-1) cells. Among these, compound 6b induced a significant reduction in the expression level of CDK9 (cyclin-dependent kinase 9)/cyclin T1 in CFPAC-1 cells concomitant with attenuation of proliferative signaling mediated by c-Raf (rapidly accelerated fibrosarcoma) and p38 MAP (mitogen-activated protein) kinases. Our findings encourage further development of novel structurally related analog of 6b to obtain more selective anticancer agent for treating pancreatic cancer.

Design, synthesis and biological evaluation of novel condensed pyrrolo[1,2-c]pyrimidines featuring morpholine moiety as PI3Kα inhibitors

Four series of condensed pyrrolo[1,2-c]pyrimidines 6a–d, 8a–d, 10a,b and 12a–e designed as PI3Kα inhibitors were synthesized and evaluated for inhibitory activity and selectivity toward different PI3K isoforms. The tested compounds displayed PI3Kα kinase inhibitory activity at either low micromolar or nanomolar level. In particular, the morpholino-pyrimidopyrrolopyrimidinones 8a–d and morpholino-pyridopyrrolopyrimidine-2-carbonitriles 12a–e proved to be highly potent and selective PI3Kα inhibitors (IC50 = 0.1–7.7 nM). Moreover, the target compounds exhibited considerable cytotoxic activity against cervical cancer cell line HeLa that over-expresses p110α (0.21–1.99 μM). Molecular modeling simulation revealed that, the designed compounds docked well into p110α active site and their complexes are stabilized by a key H-bonding with the backbone amide of Val851 as well as other favorable hydrophobic and H-bond interactions with different amino acids within the enzyme active site.

IBD-mediated oxidative cyclization of pyrimidinylhydrazones and concurrent Dimroth rearrangement: Synthesis of [1,2,4]triazolo[1,5-c]pyrimidine derivatives.

Oxidative cyclization of 6-chloro-4-pyrimidinylhydrazones 4 with iodobenzene diacetate (IBD) in dichloromethane gives rise to [1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a–o. These incipient products undergo feasible Dimroth rearrangement to furnish the isolated [1,2,4]triazolo[1,5-c]pyrimidines 6a–o in moderate to high yields.

Thioxopyrimidine in Heterocyclic Synthesis II: Novel Synthesis of Some Triazoles and Triazepine Derivatives with a Pyrimido[3,2:4,5]thieno[2,3‐d]pyrimidine Skeleton

Condensation of ethoxymethyleneamino‐thieno[2,3‐d]pyrimidines 4 with appropriate amino compounds afforded the corresponding 7‐substituted‐8‐imino‐pyrimido[3,2:4,5]thieno[2,3‐d]pyrimidines 6a, 6b, and 7 and 2‐substituted‐pyrimido[3′,2′:4,5]thieno[3,2‐e][1,2,4]triazolo[1,5‐c]pyrimidines 9a, 9b, respectively. Also, hydrazinolysis of compound 4 in ethanol which yielded the key intermediate 7‐amino‐8‐imino‐pyrimido[3,2:4,5]thieno[2,3‐d]pyrimidine (10), which can be cyclized with appropriate isothiocyanates 14a–14g in refluxing pyridine, afforded the corresponding 2‐(substituted‐amino)‐pyrimido[3′,2′:4,5]thieno[3,2‐e][1,2,4]triazolo[1,5‐c]pyramidines 15a–15g. Furthermore, intramolecular cyclization of compound (10) with appropriate 1,3‐dibromopropane and Mannich bases 18a–18c under the basic condition afforded the corresponding (tri)dihydropyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6‐b][1,2,4]triazepines 16 and 18a–18c, respectively. On the other hand, the 11‐substituted‐pyrimido[3′,2′:4,5]thieno[3,2:4,5]pyrimido[1,6‐b][1,2,4]triazepines 21a–21e were also obtained by the intramolecular cyclization of compound (10) with appropriate enaminone derivatives 19a–19e under the acidic condition.

Synthesis of novel pyrazolo[3,4-d]pyrimidine derivatives as potential anti-breast cancer agents

A series of new 1-aryl-4-benzylidenehydrazinyl-3-methylsulphanyl-pyrazolo[3,4-d]pyrimidines 6a–p was synthesized. The cytotoxic activity of the newly synthesized compounds against human breast cancer cell line, MCF7 was investigated. Most of the test compounds showed potent antitumor activity comparable to that of doxorubicin. The 1-phenyl series (6a–i) exhibited better antitumor activity than 1-(4-methoxyphenyl) series (6j–p). 4-[2-(4-Fluorobenzylidene)hydrazinyl]-3-(methylsulphanyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (6d) was the most active compound in this study with IC50 equal to 7.5 nM.

Synthesis and Antimicrobial Activity of Some S-β-D-Glucosides of 4-Mercaptopyrimidine

5-Acetyl-2-aryl-6-methyl-4-(2,3,4,6-tetra- O -acetyl-β-D-glucopyranosylmercapto)pyramidines 3a–c were obtained by the reaction of 5-acetyl-2-aryl-6-methyl-pyrimidine thiol 1a–c with 2,3,4,6-tetra- O -acetyl-α-D-glucopyranosyl bromide (2) in aq. KOH/acetone. The reaction of 1a–c with peracetylated galactose 5 and peracetylated ribose 8 under MW irradiation gave 5-acetyl-2-aryl-6-methyl-4-(2,3,4,6-tetra- O -acetyl-β-D-galactopyranosylmercapto)pyrimidine 6a–c and 5-acetyl-2-aryl-6-methyl-4-(2,3,5-tri- O -acetyl-β-D-ribofuranosylmercapto)pyrimidines 9a–c. The deprotection of 3a–c, 6a–c, and 9a–c in the presence of methanol and TEA/H2O yielded the deprotected products 4a–c, 7a–c, and 10a–c. The structures of the compounds were confirmed by using IR, 1H, 13C spectra and microanalysis. Selected members of these compounds were screened for antimicrobial activity.

Studies on aminopyrazoles: antibacterial activity of some novel pyrazolo[1,5- a]pyrimidines containing sulfonamido moieties

Hydrazones 2a– d were prepared from diazotiazation of sulfanilamide or its derivatives followed by coupling with ethyl cyanoacetate. 3-Aminopyrazoles 3a– d were obtained by refluxing of 2a– d with hydrazine hydrate in ethanol. [Bis(methylthio)methylene]malononitrile ( 4) was reacted with aminopyrazoles 3a– d in refluxing DMF containing triethylamine to yield the novel pyrazolo[1,5- a]pyrimidines 6a– d. The anilino derivatives 8a– h were obtained by fusion of compounds 6a– d with aromatic amines. When compounds 6a, c, d were subjected to the reaction with hydrazine hydrate, the hydrazino derivatives 9a– c were isolated. Also, the aminopyrazoles 3 were reacted with some electrophiles such as arylidenemalononitriles, ethoxymethylene malononitrile and ethyl ethoxymethylene cyanoacetate to yield the novel substituted pyrazolo[1,5- a]pyrimidines 13, 17 and 19, respectively. Structures of the new compounds were established by their elemental analyses and spectral data. Most of these compounds were also tested in vitro for their antibacterial activity against some Gram positive and Gram negative bacteria.

Studies on Uracils: Synthesis of Novel Uracil Analogues via 1,5- and 1,6-Intramolecular Cycloaddition Reactions

6-(Tertiary amino)uracils 1 react with dimethyl acetylenedicarboxylate (DMAD) to afford 5,6-dihydropyrrolo[2,3-d]pyrimidines 3a and 3b and the tricyclic analogues 3c–fvia 1,5-electrocyclisation in excellent yields, whereas suitably functionalized uracil derivatives 5 undergo intramolecular 1,6-cycloaddition reactions to afford 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines 6a and 6b and the tricyclic analogues 6c–h in high yields.

Aminopyrimidines and Derivatives. 221. Synthesis of 3-Glycopyrano-Syl-vic-Triazolo [4,5-d]Pyrimidines, 7-Glycopyranosyl-Pyrrolo [2,3-d]PY-Rimidines and 4-Glycopyranosylamino-Furo [2,3-d]Pyrimidines2

Abstract Reaction between 4-β-D-(O-acetyl)glycopyranosylaminopyrimidines 1 and chloracetylchloride yields the corresponding 5-α-chloracetyl derivatives 2, the hydrolysis products 3 and the corresponding 5-α-chloracetyl derivative of compounds 3. The former compounds were cyclized to the corresponding 7- β-D-glycopyranosyl-pyrrolo[2,3-d]pyrimidines 5 (2a yields 5,6-dihydro-4-β-D-(2,3,4,6-tetra-O-acetyl)glucopy-ranosylamino-2-methoxy-5-oxo-furo[2,3-d]pyrimidine 6a); the second ones to 3-β-D-(O-acetyl)glycopyranosyl-vic-triazolo[4,5-d] pyrimidines 10, and the last one to 4-β-D-(O-acetyl)glycopyranosylamino-furo[2,3-d] pyrimidines 7. The anticancer activity of some of these products is noticed.

Synthese neuartiger triazoloanellierter 8‐Azapurine

Synthesis of New Triazolo‐Annulated 8‐AzapurinesTreatment of the 5‐amino‐4‐cyano‐1,2,3‐triazoles 1a–f with triethyl orthoformate and orthoacetate 2 gives the ethoxymethyleneamino‐1,2,3‐triazoles 3a–f which react with hydrazine hydrate at room temperature to yield the 1‐amino‐6‐imino‐8‐azapurines 4a–f. The pyrimidines 6a–I are obtained from 4a–f by reaction with triethyl orthoacetate and orthoformate 5.

Heteroaromatic Acetonitriles, I. Reactions of 5‐Substituted (4H‐1,2,4‐Triazol‐3‐yl)acetonitriles with Salicylaldehyde

AbstractOn heating of the (4H‐1,2,4‐triazol‐3‐yl)acetonitriles 2a and 2b with salicylaldehyde (1) in the presence of bases the 12H‐[1]benzopyrano[3,2‐e]‐1,2,4‐triazolo[4,3‐c]pyrimidines 6a and 6b were obtained. A mechanism for these reaction is proposed.

Thiazolsynthesen mit N‐Cyanimidsäureestern oder 3‐Cyanisoharnstoffen und Thioglycolsäurederivaten

Thiazoles from N‐Cyanoimidates or 3‐Cyanoisoureas and Thioglycolic Acid DerivativesNovel thiazoles 3a–g, 4a–d are synthesized from N‐cyanoimidates and 3‐cyanoisoureas of type 1a–m and thioglycolic acid methyl ester (2a) as well as the amide (2b). The limitations of the reaction are outlined. The products are further converted into thiazolo[4,5‐d]pyrimidines 6a–d and thiazolo [4,5‐d]‐1,2,3‐triazinones 7a–c.