Solid phase synthesis of structurally diverse pyrimido[4,5-d] pyrimidines for the potential use in combinatorial chemistry

An efficient solid phase synthesis of pyrimido[4,5-d]pyrimidine derivatives is described. Reaction of polymer-bound pyrimidine 1 with urea or thiourea followed by cleavage from the support provided 4-aminopyrimido[4,5-d]pyrimidines 4 and 5 while treatment of 6 with phenyl isocyanate or phenyl isothiocyanate followed by cleavage from resin afforded 3-phenylpyrimido[4,5-d]pyrimidines 9 and 10.     

Novel hepatitis C virus replicon inhibitors: synthesis and structure-activity relationships of fused pyrimidine derivatives

The synthesis of several pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine analogs is described with one such analog possessing subnanomolar potency in both genotype 1a and 1b cell culture HCV replicon assays.     

Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as selective human A(1) adenosine receptor ligands

A series of pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays to determine their affinities for the human adenosine A(1), A(2A), A(2B) and A(3) receptors. Results indicated that this scaffold is appropriate for adenosine receptor subtype A(1) ligands and that the best arranged groups around this scaffold are 3- and 4-pyridinyl at position 1, benzyl at position 3, hydrogen at position 6 and 3-thienyl or phenyl at position 9. The most interesting compounds showed K(i) for A1 in the nanomolar range and an appreciable selectivity for other receptor subtypes.     

Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents

A number of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives were synthesized and screened for antibacterial and antifungal activities. All the synthesized compounds showed the potent antimicrobial activity. The quantitative structure-activity relationship investigation was applied to find a correlation between the different physicochemical parameters of the compounds studied and their biological activity.     

Synthesis, analgesic, anti-inflammatory, and antimicrobial activity of some novel pyrimido[4,5-b]quinolin-4-ones

Novel series of pyrimido[4,5-b]quinolines (3a-c), triazolo[4',3':1,2]pyrimido[4,5-b]-quinolines (7a-e, 9, and 14), tetrazolo[4',3':1,2]pyrimido[4,5-b]quinolin-5-one (13), [1,3]-pyrazolo[3',2':1,2]pyrimido[4,5-b]quinolines (12a and 12b), and 2-pyrazolyl-pyrimido[4,5-b]-quinolines (15, 16a, 16b, and 19) have been synthesized. Some of the new compounds were tested against various bacteria and fungi species. In addition, the analgesic and anti-inflammatory activities are reported. Compounds 8 and 9a possess high activity toward the fungi as compared with the reference drug Nystatin. The tested compounds 5 and 8 have moderate anti-inflammatory activities. Moreover compounds 5, 8, 10, and 16a, have activities higher than the reference drug in peripheral analgesic activity testing, Compounds 5, 7a, 11a, and 16a have potencies as the reference drug in central analgesic activity testing.     

Synthesis of Novel Polycyclic Nucleoside Analogs

Abstract

We have synthesized polycyclic nucleoside derivatives by a novel, one pot procedure by reacting 4-0-TPS-pyrimidine nucleosides with aromatic diamines. The reaction is limited in scope but provides easy access to certain previously unknown heterocyclic ring systems.₂ 4-0-Triisopro- pylphenylsulfonyl-pyrimidine nucleosides were reacted with aromatic diamines leading to fused, polycyclic ring systems: o-phenylenediamine yielded the pyrimido[1,6-a]benzimidazole, 2.3- diaminonaphthalene gave the naphth[2′,3′:4,5]imidam [1.2-flpyrimidine and 1.8-diaminonaph- thalene led to the pyrimido[l,6-a]perimidine ring system. The reaction is unique because two connected nucleophilic centers react with the pyrimidine nucleoside to form an extended ring system. However, reactions of pyrimidine nucleosides with electrophiles are well known. E.g., reaction of cytidine and adenosine with bromoacetaldehyde yields ethenocytidine and ethenoadenosine) and on reaction of cytidine with 1′-methylthiaminium salts dipyrimido[1,6-a:4′,5′-d]pyrimidine derivatives are obtained.₄ Other polycyclic bases have been made from cytidine and adenosine by photochemical reactions₅.     

Synthesis and antiviral activity of 4,6-disubstituted pyrimido[4,5-b]indole ribonucleosides

A series of new pyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 4 has been prepared by selective Pd-catalyzed cross-coupling reactions of the corresponding protected 4,6-dichloropyrimido[4,5-b]indole ribonucleoside with (het)arylboronic acids or stannanes followed by deprotection. Further cross-couplings under harsher conditions and employing X-Phos ligand proceeded at the position 6 leading to 4,6-disubstituted pyrimido[4,5-b]indole ribonucleosides. Some of these compounds displayed antiviral activity against Dengue virus.     

A new therapeutic approach in Parkinson’s disease: Some novel quinazoline derivatives as dual selective phosphodiesterase 1 inhibitors and anti-inflammatory agents

The increasing life expectancy in our population makes Parkinson’s disease (PD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that selective phosphodiesterase 1 (PDE1) inhibitors and anti-inflammatory agents might be effective in treating PD. Therefore, a novel 1,2,9,11-tetrasubstituted-7H-thieno[2′,3′:4,5]pyrimido[6,1-b]-quinazolin-7-one (1–15) and 1,3,10,12-tetrasubstituted-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one (16–36) derivatives were synthesized by reported method and investigated for their ability to inhibit PDE1. Most of the synthesized compounds have shown good activity against PDE1 and were less effective than 3-isobutyl-1-methylxanthine. All the compounds were also tested for their in vitro anti-inflammatory activity by carrageenan-induced oedema in rats. In addition, ulcerogenic activity was determined. The combined anti-inflammatory data from in vitro animal model showed that compounds, 9,11-dibromo-1-(2-furyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 23, 9,11-dibromo-1-(4-methoxy-phenyl)-3-phenyl-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 24, 9,11-dibromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 29 and 9-bromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 36 exhibited even more potent anti-inflammatory activity and low gastric ulceration incidence compare to reference standard Indomethacin. Since compound 23, 24, 29 and 36 exhibits both anti-inflammatory activity and PDE1 inhibition, it needs further detailed studies.     

SAR comparative studies on pyrimido[4,5-b][1,4] benzothiazine derivatives as 15-lipoxygenase inhibitors, using ab initio calculations

The enzyme inhibitory activity of a new group of 2-substituted pyrimido[4,5-b][1,4]benzothiazines on soybean 15-lipoxygenase (15-LO) was evaluated and compared with those of their 4-methyl analogs using ab initio calculations. The results of these studies showed that the lack of 4-methyl substituent in the pyrimido[4,5-b][1,4] benzothiazine molecules greatly reduces their 15-LO inhibitory activities.     

Synthesis, antioxidant and toxicological study of novel pyrimido quinoline derivatives from 4-hydroxy-3-acyl quinolin-2-one

A series of novel pyrimido and other fused quinoline derivatives like 4-methyl pyrimido [5,4-c]quinoline-2,5(1H,6H)-dione (4a), 4-methyl-2-thioxo-1,2-dihydropyrimido [5,4-c]quinoline-5(6H)-one (4b), 2-amino-4-methyl-1,2-dihydropyrimido [5,4-c]quinolin-5(6H)-one (4c), 3-methylisoxazolo [4,5-c]quinolin-4(5H)-one (4d), 3-methyl-1H-pyrazolo [4,3-c]quinoline-4(5H)-one (5e), 5-methyl-1H-[1,2,4] triazepino [6,5-c]quinoline-2,6(3H,7H)-dione (5f), 5-methyl-2-thioxo-2,3-dihydro-1H-[1,2,4]triazepino [6,5-c]quinolin-6(7H)-one (5 g) were synthesized regioselectively from 4-hydroxy-3-acyl quinolin-2-one 3. They were screened for their in vitro antioxidant activities against radical scavenging capacity using DPPH(), Trolox equivalent antioxidant capacity (TEAC), total antioxidant activity by FRAP, superoxide radical (O(2)(°-)) scavenging activity, metal chelating activity and nitric oxide scavenging activity. Among the compounds screened, 4c and 5 g exhibited significant antioxidant activities.     

Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors

Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH? substituents inhibited human (h) TS (IC?? =0.26-0.8 μM), but not hDHFR. Substitution of the 2-CH? with a 2-NH? increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC?? = 0.09-0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.     

Synthesis and pharmacological assessment of derivatives of isoxazolo[4,5-d]pyrimidine

A series of new 5-alkyl and 5-arylisoxazolo[4,5-d]pyrimidinones (5a-g, 6-8) were prepared from 4-amino-3-oxo-isoxazolidine-5-carboxylic acid amide. Some of the aryl derivatives of isoxazolo[4,5-d]pyrimidine were tested pharmacologically in comparison with Diazepam. Compounds 5b-d and 7 demonstrated interesting anxiolytic activity.     

New pyrimido[5,4-b]indoles and [1]benzothieno[3,2-d]pyrimidines: high affinity ligands for the alpha(1)-adrenoceptor subtypes

A number of new pyrimido[5,4-b]indole and [1]benzothieno[3,2-d]pyrimidine derivatives were synthesized and evaluated for their binding and functional properties at alpha(1)-adrenergic receptor (alpha(1)-AR) subtypes. They behaved as potent alpha(1)-AR antagonists. In binding experiments, some of them (RC24 and RC23) showed very high affinity for the alpha(1D)-AR subtype.     

Anticytokinin activity of 4-substituted triazolo[4,5-d]pyrimidines and 4-substituted pyrazolo[3,4-d]pyrimidines

The synthesis and physiological activity of some novel 4-substituted triazolo[4,5-d]pyrimidines and 4-substituted pyrazolo[3,4-d]pyrimidines are described. Most of the compounds possessed high anticytokinin activity towards purine (benzyladenine) and phenylurea (4-PU-30) type cytokinins. 1-Benzyl-4-ethoxycarbonylpiperazinyl-1H-1,2,3-triazolo[4,5-d]pyrimidine almost completely removed cytokinin stimulated effects—betacyanin synthesis in Amaranthus caudatus cotyledons; growth of radish cotyledons and retention of chlorophyll in leaf explants. Some chemical structurephysiological activity relationships have been established.     

2,4-Diamino-9H-pyrimido[4,5-b]indol-5-ols: synthesis, in vitro cytotoxic activity, and QSAR investigations

A series of novel 2,4-diaminopyrimido[4,5-b]indol-6-ols has been synthesized and the in vitro cytotoxic activities were evaluated against four human cancer cell lines originating from solid tumors. An increase in activity was observed when a heteroaromatic ring was annulated on side g of the pyrimido[4,5-b]indole system to give compounds with activities comparable to ellipticine and cisplatin. To understand the experimental cytotoxic activities, QSAR investigations were performed, which showed a very good linearity between the experimental and predicted IC(50).     

Synthesis of new indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones as potential antitumor agents

Novel racemic indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones 3-29 were obtained regioselectivily from the reaction of 5,6-diamino-3,4-dihydropyrimidin-4-ones 1 and 2-arylideneindandiones 2 as reagents. These compounds have been evaluated at the US National Cancer Institute (NCI) for their ability to inhibit approximately 60 different human tumor cell lines, where 5 and 6 presented remarkable activity against 57 and 48 cancer cell lines, respectively, with the most important GI(50) values ranging from 0.49 to 1.46 microM, in vitro assay.     

Synthesis of imidazo[4,5-d][1,3]thiazine ribosides and related compounds of biological interest

Several tri-O -acetyl-1-beta-D -ribofuranosyl- and 2-acetoxyethoxymethylimidazo[4,5-d][1,3]thiazine derivatives 5-10 were synthesized from imidazo[4,5-d][1,3]thiazine 4 and tetra-O -acetyl-beta-D -ribofuranose or 2-acetoxyethoxymethyl acetate by fusion method. In each case, depending on the substituent on position 5 of thiazine skeleton, only N3 isomer or both N1 and N3 isomers (in different ratios) were obtained.     

2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one as a structurally new NK1 antagonist

The structurally novel pyrimido[4,5-b][1,5]oxazocine derivative 3, a hybrid compound of pyrido[4,3-b]- and [2,3-b]-1,5-oxazocine (1 and 2, respectively), was designed and synthesized. We examined the atropisomeric property and the NK1 antagonist activity of 3. Compound 3 was found to possess both a feature of 1, free rotation about the biaryl bond, and a feature of 2, potent in vivo activity.     

Design,synthesis, and structure–activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells

To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2–8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2–8. Compounds 2 and 6 had two-digit nanomolar potency (IC₅₀) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles.     

8-Phosphorus substituted isosteres of purine and deazapurines.

Synthesis of 8-phosphorus substituted isosteres of purine [pyrimidino (4,5-d)-1,3,2-diazaphosphole], 1-deazapurine [pyridino (2,3-d)-1,3,2-diazaphosphole] and 3-deazapurine [pyridino (4,5-d)-1,3,2-diazaphosphole] has been achieved by the reaction of equimolar amounts of triphenylphosphite and 4,5-diaminopyrimidine, 2,3-diaminopyridine and 3,4-diaminopyridine, respectively. These compounds hydrolyzed (cleavage of the phosphorus-nitrogen bounds) in aqueous solutions to provide the corresponding diaminopyrimidine or diaminopyridines. These three new basic ring systems constitute the first reported synthesis of purines in which ring carbon atom is substituted with a phosphorus atom. 8-Phosphorus substituted purine at a concentration of 4 X 10(-4)M caused a 50% inhibition in the growth of leukemia L1210 cells in culture. The biochemical rationale for the synthesis of these compounds is discussed.