Pyrimido-pyrimidine Derivatives Research Articles

Synthesis, Antibacterial, Enzyme Inhibitory, and Molecular Docking Studies of Pyrimido-Pyrimidine Derivatives as Urease Inhibitors

Synthesis, Antibacterial, Enzyme Inhibitory, and Molecular Docking Studies of Pyrimido-Pyrimidine Derivatives as Urease Inhibitors

Theoretical study of the effect of the solvent on the electronic properties of pyrimidopyrimidine derivatives

Quantum calculations were carried out on some pyrimidopyrimidine tautomeric heterocyclic derivatives both in gas phase and in solution in order to study the influence of the migration of hydrogen on their electronic and structural properties as well to highlight the effect of the solvent on the process of tautomerism. Results indicate that the electronic properties of the studied heterocycles are influenced by the nature of the solvent used. All tautomeric forms are more stable in H2O and DMSO than in CHCl3 and in the gas phase. The predominance of the di-ketone form in gas phase and solution is observed.

Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis.

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure–activity relationships (SAR) were explained with the assistance of molecular docking.

Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors.

This work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-d]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references. Six novel derivatives possess IC50 values on PI3Kα between 3 and 10 nM. The compounds with the best efficiencies on PI3K and mTOR induced micromolar cytotoxicity on cancer cell lines possessing an overactivated PI3K pathway.

Synthesis, characterization, computational chemical studies and antiproliferative activity of some heterocyclic systems derived from 3-(3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chromen-2-one

The key material, 3-(3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chromen-2-one (3) was synthesized and its behavior toward malononitrile, hydrazine, thiourea, thiosemicarbazide, 2-aminoaniline, and 6-aminothiouracil was investigated aiming to synthesize a new series of pyrazole-based heterocycles, namely, pyranochromene, diazepine, pyrimidochromene, triazepine, benzodiazepine, pyrimidine, and pyrimidopyrimidine derivatives. Density functional theory based on quantum chemical computation outline the structure optimization of the intermediate that reacted to afford the desired product. The antiproliferative screening against HePG-2 and MCF-7 cancer cell lines disclosed that the most potent compounds against two cell lines were 9 and 17 as compared to doxorubicin which may be due to their presence in more tautomeric structures. Also, the minimized energy, dipole moment, ionization potential, transferred electrons, and charge density distribution revealed that the greater value of 0.126 and 0.8 for pyrazole derivatives 9 and 17, respectively, indicates the maximum transfer of electron and hence, greater tendency of scavenging radicals and rapidly reduce oxygen to superoxide.

Bicyclic Basic Merbarone Analogues as Antiproliferative Agents.

Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase IIα. To further extend the structure–activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3–6 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure–activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase IIα-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation.

Synthesis and antioxidant screening of new 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl amide derivatives and some pyrazole-based heterocycles

The high functionality compound namely 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl chloride (1) was utilized as a building block synthon via reactions with some nitrogen and sulfur nucleophilic reagents. The present work was planned to study the effect of 2-cyano group on the reactivity and stability of C2–C3 double bond toward different strong-to-weak nucleophiles, in addition to its facility of nucleophilic addition at C2–C3 double bond to construct new heterocyclic derivatives. The proclivity toward some mono-, 1,2-, 1,3-, 1,4-, and 1,5-binucleophiles was investigated. The reaction with 2-cyanoacetohydrazide was mainly dependent on the reaction conditions. Some new heterocycles integrated with pyrazole scaffold were successfully synthesized, such as benzoxazinone, indoline, isoindoline, pyrazolone, chromene, and pyrimidopyrimidine derivatives. Some of the newly synthesized compounds were screened for their antioxidant activity using ABTS method, and the results revealed that some compounds exhibited promising inhibitory antioxidant activity.

Design and synthesis of novel pyrimido[5,4-d]pyrimidine derivatives as GPR119 agonist for treatment of type 2 diabetes

We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC0–2h) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC0–2h at the dose of 300 mg/kg.

ChemInform Abstract: Synthesis, Characterization, and in vitro Antimicrobial Activity of a New Class of 7‐Substituted Amino‐2‐phenyl‐3H‐pyrimido[4,5‐d]pyrimidin‐4‐one.

AbstractThe members of the new class of pyrimido pyrimidine derivatives (I) display pronounced in vitro antibacterial and antifungal activities.

Further SAR studies on bicyclic basic merbarone analogues as potent antiproliferative agents

Pyrimidopyrimidine derivatives 1 were prepared as rigid thioanalogues of merbarone (a catalytic topoisomerase II inhibitor) and screened as antiproliferative agents against different tumor cell lines. A number of the synthesized compounds emerged as cytotoxic in cell-based assays (MT-4, HeLa and MCF-7 cells) at low micromolar concentrations. In a National Cancer Institute screening, selected member of the series showed a broad spectrum of antiproliferative activity against various tumours (melanoma, renal, CNS, colon and breast cancers). The acid–base and steric properties of the substituent at position 7 of the pyrimidopyrimidine scaffold deeply affected potency. Enzymatic assays evidenced that a subset of tested derivatives efficiently inhibit topoisomerase IIα accordingly to merbarone mechanism of action. However this property does not fully rationalize the cytotoxicity data of the full ligand panel, suggesting that different target(s) should be additionally involved.

Synthesis, Characterization, andIn VitroAntimicrobial Activity of a New Class of 7-Substituted Amino-2-phenyl-3H-pyrimido[4,5-d]pyrimidin-4-one

A new class of pyrimido pyrimidine derivatives that exhibits in vitro antimicrobial activity was synthesized. The protection of amino group in the compound 1 with acetic anhydride, followed by the reaction with POCl3, gave 3. The reaction of 3 with different substituted phenyl methanediamine in dry TEA under inert atmosphere led to the formation of 4. Deprotection of 4 followed by refluxion with different acid chlorides yielded title compounds 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j, 6k, 6l, 6m in good yields. The identities of these compounds were confirmed following elemental analysis, IR, 1H, 13C NMR, and mass spectral studies. All the title compounds exhibited pronounced in vitro antibacterial and antifungal activities.

Novel pyrimidopyrimidine derivatives for inhibition of cellular proliferation and motility induced by h-prune in breast cancer

The human (h)-prune protein is a member of the DHH protein superfamily and it has a cAMP phosphodiesterase activity. Its overexpression in breast, colorectal and gastric cancers correlates with depth of invasion and a high degree of lymph-node metastasis. One mechanism by which h-prune stimulates cell motility and metastasis processes is through its phosphodiesterase activity, which can be suppressed by dipyridamole, a pyrimido[5,4-d]pyrimidine analogue. To obtain new and more potent agents that have high specificity towards inhibition of this h-prune activity, we followed structure–activity-relationship methodologies starting from dipyridamole and synthesised eight new pyrimido–pyrimidine derivatives. We analysed these newly generated compounds for specificity towards h-prune activities in vitro in cellular models using scintillation proximity assay for cAMP-PDE activity, cell index in cell proliferation assays and transwell methodology for two-dimensional cell migration in a top-down strategy of selection. Our findings show that two pyrimido[5,4-d]pyrimidine compounds are more effective than dipyridamole in two highly metastatic cellular models of breast cancer in vitro. Future studies will assess their therapeutic effectiveness against breast and other cancers where there is over-expression of h-prune, and in ad-hoc, proof of concept, animal models.

Synthesis of Some New Pyrimidine and Pyrimido[4,5-d]pyrimidine Derivatives

A convenient synthesis of a series of pyrimidine carbonitrile, thiopyrimidine, and pyrimidopyrimidine derivatives, via the reactions of the versatile, readily accessible 6-aryl-4-oxo-2-thioxo-hexahydro-pyrimidine-5-carbonitrile with the appropriate reagents, is described.

Facile Synthesis of Pyrazolo[3,4‐d]pyrimidines and Pyrimido[4,5‐d]pyrimidin‐4‐one Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Facile Synthesis of Pyrazolo[3,4‐d]pyrimidines and Pyrimido[4,5‐d]pyrimidin‐4‐one Derivatives

Pyrazolopyrimidine and pyrimidopyrimidine derivatives have shown a wide range of biological activities such as acting as A1 adenosine receptors, kinase insert domain receptor (KDR), Rous sarcoma oncogene (Src), epidermal growth factor receptor (EGFR), antiproliferative, dihydrofolate reductase (DHFR), antimicrobial, antifungal, and lipid peroxidation. Because of this wide range of activities, we have synthesized pyrazolo[3,4‐d]pyrimidines and pyrimido[4,5‐d]pyrimidin‐4‐one derivatives.

Inhibition of epidermal growth factor receptor activity by two pyrimidopyrimidine derivatives.

Overexpression of the epidermal growth factor receptors (EGFRs) and human epidermal growth factor receptor 2 occurs frequently in human cancers and is associated with aggressive tumor behavior and poor patient prognosis. We have investigated the effects in vitro and in vivo of a new class of inhibitor molecules on the growth of several human cancer cell lines. BIBX1382 [N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine] and BIBU1361 [(3-chloro-4-fluoro-phenyl)-[6-(4-diethylaminomethyl-piperidin-1yl)-pyrimido[5,4-d]pyrimidin-4-yl]-amine] are two new selective EGFR kinase inhibitors that do not block the activity of other tyrosine kinases. BIBU1361 blocked epidermal growth factor-induced phosphorylation of EGFR and also prevented downstream responses such as mitogen-activated protein kinase kinase (MAPK/extracellular signal-regulated kinase kinase) and MAPK activation in cells. In accordance with these observations thymidine incorporation into EGFR-expressing KB cells was selectively and potently inhibited by BIBX1382 and BIBU1361 with half-maximally effective doses in the nanomolar range. Oral administration of these compounds inhibited the growth of established human xenografts in athymic mice, including vulval and head and neck squamous cell carcinomas. Tumor growth inhibition by BIBX1382 coincided with reduced pEGFR and Ki-67 levels in vivo, which is in accordance with the expected effect of EGFR inhibitors. Collectively, these results show that the structural class of pyrimidopyrimidines, exemplified here by BIBX1382 and BIBU1361, represents an interesting scaffold for the design of EGFR inhibitors.

Versatile, convenient synthesis of pyrimido[1,2,3- cd]purinediones

The alkylation of 3-substituted cycloalkylcarboxamido-6-aminouracil derivatives with 3-bromo-1-propanol followed by ring closure yields 1,3,8-trisubstituted xanthine derivatives bearing a polar hydroxyl group. Use of the more reactive 1,3-dibromopropane or homologous dibromoalkanes for the alkylation reaction results in simultaneous alkylation at N1 and the exocyclic amino group (N 6) yielding imidazo-, pyrimido- and diazepino-pyrimidine derivatives. The pyrimidopyrimidine derivatives can subsequently be cyclised using hexamethyldisilazane at high temperature affording an easy, convenient and general access to tricyclic pyrimido[1,2,3- cd]purinediones. Alternatively, 3-substituted 6-amino-5-benzylideneaminouracil derivatives can be reacted with 1,3-dibromopropane followed by an oxidative cyclisation using thionyl chloride to obtain the desired tricyclic pyrimido[1,2,3- cd]purinediones, which are sterically fixed analogues of pharmacologically active purine derivatives.

The pyrimido-pyrimidine derivatives, dipyridamole, mopidamol and RA-642, prevent from retinal vascular defects in experimental diabetes mellitus

We compared the effects of dipyridamole, RA-642, and mopidamol on platelet activity and thromboxane/prostacyclin balance in relation to the degree of retinal vascularization in a model of experimental streptozotocin-induced diabetes in rats. After 3 months, collagen-induced platelet aggregation in whole blood was 25% higher in diabetic animals than in nondiabetics. Dipyridamole inhibited 43% platelet aggregation, mopidamol 39%, and RA-642 36%. Platelet production of thromboxane B 2 was 87% higher in untreated diabetic rats. Mopidamol and RA-642 produced a 46% and 41% inhibition of thromboxane B 2. Dipyridamole did not inhibited thromboxane B 2 synthesis. Aortic production of 6-keto-PGF 1α was 43% lower in untreated diabetic animals and showed no change after treatment with either mopidamol or RA-642. In contrast, dipyridamole caused a 90% increase in aortic production of prostacyclin. Computerized analysis of retinal vascularization showed that untreated diabetic rats had a 81% decrease in the area occupied by peroxidase-labelled vessels as compared with nondiabetics. Treatment with dipyridamole, mopidamol, and RA-642 caused 2.5-fold, 2.8-fold and four-fold increases, respectively, in the percentage of retinal surface occupied by peroxidase-labelled vessels. Differences in retinal vascularization between diabetic animals given RA-642 and nondiabetic controls were negligible.

The pyrimido-pyrimidine derivatives, dipyridamole and RA-642, reduce opacification of crystalline lens in diabetic rats.

We assessed the effect of dipyridamole, RA-642 and mopidamol, on lenticular opacities in a model of experimental diabetic cataracts in rats. All three pyrimido-pyrimidine derivatives caused a statistically significant reduction of opacification in crystalline lens as compared with untreated diabetic animals. The production of superoxide anions (phenazine methosulphate [PMS]-induced nitroblue tetrazolium [NBT] reduction) showed a decrease of 81.6%, 78.9% and 1.8% in lens tissue homogenates from rats treated with dipyridamole, RA-642 and mopidamol, respectively. Dipyridamole and RA-642 produced a statistically significant inhibition (50% and 64.8%, respectively) of lipid peroxidation (ferrous sulphate and ascorbic acid [FeAs]-induced malondialdehyde [MDA] production) as compared with the group of untreated diabetic rats. Mopidamol did not exert any inhibitory effect on lipid peroxidation. There was a statistically significant correlation between opacification of lens and PMS-induced NBT reduction and FeAs-induced MDA production. We conclude that the protective effect of dipyridamole and RA-642 from free radical damage to crystalline lens in the model of experimental diabetes used in this study, is the result of the antioxidant action of these compounds. The effect exerted by mopidamol, however, suggest a possible complementary effect of the pyrimido-pyrimidine derivatives through interaction with other mechanisms (e.g., the sorbitol pathway) implicated in the development of cataracts.

Differential effects of the pyrimido-pyrimidine derivatives, dipyridamole and mopidamol, on platelet and vascular cyclooxygenase activity

The chronic administration of 10 mg/kg/day of dipyridamole to rats produced 33.7% inhibition of platelet aggregation induced with ADP and a 93% increase in 6-keto-prostaglandin F 1 α (6-keto-PGF 1 α ) in vascular samples, versus saline-treated rats. Mopidamol, 8.3 mg/kg/day, caused 50.6% inhibition of ADP-induced platelet aggregation, 37.6% inhibition of aggregation induced with arachidonic acid, a 47.6% decrease in serum levels of thromboxane B 2 and a 23.7% increase in the vascular production of 6-keto-PGF 1 α , versus saline-treated rats. Dipyridamole showed a higher in vitro anti-aggregating effect in whole blood (IC 50 6.6 μM) than in platelet-rich plasma (PRP) (IC 50, 210μM), when ADP was used as inducer, and had no effect in the presence of arachidonic acid. Mopidamol exerted a similar effect in whole blood (IC 50 3.7–20 μM, depending on the inducer) and PRP (IC 50 11-17.3 μM), and showed a dose-dependent inhibition of platelet aggregation and thromboxane B 2 synthesis induced with arachidonic acid (IC 50 16.8–22.3 μM). Mopidamol also inhibited enzymatically induced lipid peroxidation) (IC 50 89 ± 5.9 μmol/L) and had no effect on free radical-induced lipid peroxidation. The dose-dependent increase in 6-keto-PGF 1 α in vascular samples after incubation with dipyridamole showed a negative linear correlation with inhibition of lipid peroxidation ( τ 2 = 0.77). It is concluded that the phosphodiesterase inhibitors, dipyridamole and mopidamol, interfere in a different manner with platelet function. It seems that mopidamol may also exert a selective effect on platelet thromboxane synthesis.