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  1. Fluorescence studies of selected 2-alkylaminopyrimidines
    Abdullah Z, Tahir NM, Abas MR, Aiyub Z, Low BK
    Molecules, 2004 Jun 30;9(7):520-6.
    PMID: 18007451
    The reactions of 2-chloropyrimidine with methylamine, ethylamine and piperidine gave the corresponding 2-N-methylamino-, 2-N-ethylamino- and 2N- piperidinopyrimidines, respectively. The fluorescence properties of these alkylamino derivatives in chloroform, ethyl acetate, carbon tetrachloride, acetone, ether, ethanol and methanol were studied. All the alkylamino derivatives showed the highest fluorescence intensity in polar protic solvents; thus 2-N-methylaminopyrimidine (highest fluorescence intensity at 377 nm when excited at 282 nm) and 2-N-ethylaminopyrimidine (highest fluorescence intensity at 375 nm, when excited at 286 nm) showed the highest fluorescence in methanol. In ethanol, 2-N-piperidinopyrimidine showed a fluorescence peak at 403 nm when excited at 360 nm and in chloroform it fluoresced at 392 nm when excited at 356 nm.
    Matched MeSH terms: Pyrimidines/chemistry*
  2. Correlation between polar surface area and bioferroelectricity in DNA and RNA nucleobases
    Yam SC, Zain SM, Sanghiran Lee V, Chew KH
    Eur Phys J E Soft Matter, 2018 Jul 18;41(7):86.
    PMID: 30014219 DOI: 10.1140/epje/i2018-11696-5
    We have performed computational molecular modelling to study the polarization switching and hysteresis loop behaviours of DNA and RNA nucleobases using the PM3 semi-empirical quantum mechanical approaches. All the nucleobases: adenine (A), thymine (T), guanine (G), cytosine (C), and uracil (U) were modelled. Our study indicates that all the nucleobases exhibit a zero-field polarization due to the presence of polar atoms or molecules such as amidogen and carbonyl. The shape of polarization P versus an applied electric field E hysteresis loop is square, implying typical ferroelectrics behaviour. The total energy U as a function of an applied electric field E exhibits a butterfly-like loop. The presence of zero-field polarization and ferroelectrics hysteresis loop behaviours in nucleobases may support the hypothesis of the existence of bioferroelectricity in DNA and RNA. We also found an interesting relationship between the minimum electric field required for switching [Formula: see text] and the ratio of the topological polar surface area (TPSA) to the total surface area (TSA) of a nucleobase. In particular, the [Formula: see text] of a nucleobase is inversely proportional to the TPSA/TSA ratio. This work may provide useful information for understanding the possible existence of ferroelectricity in biomaterials.
    Matched MeSH terms: Pyrimidines/chemistry*
  3. Ethyl-4-(aryl)-6-methyl-2-(oxo/thio)-3,4-dihydro-1H-pyrimidine-5-carboxylates: Silica supported bismuth(III)triflate catalyzed synthesis and antioxidant activity
    Gajjala RR, Chinta RR, Gopireddy VSR, Poola S, Balam SK, Chintha V, et al.
    Bioorg Chem, 2022 Dec;129:106205.
    PMID: 36265354 DOI: 10.1016/j.bioorg.2022.106205
    Novel ethyl-4-(aryl)-6-methyl-2-(oxo/thio)-3,4-dihydro-1H-pyrimidine-5-carboxylates were synthesized from one-pot, three-component Biginelli reaction of aryl aldehydes, ethyl acetoacetate and urea/ thiourea by catalytic action of silica supported Bismuth(III) triflate, a Lewis acid. All the synthesized compounds were structurally characterized by spectral (IR, 1H NMR & 13C NMR spectroscopic and Mass spectrometric) and elemental (C, H & N) analyses. The present protocol has deserved novel as, formed the products in high yields with short reaction times, involved eco-friendly methodology and reusable heterogeneous Lewis acid catalyst. The title compounds were screened for in vitro DPPH free radical scavenging antioxidant activity and identified 4i, 4j, 4h & 4f as potential antioxidants. The obtained in vitro results were correlated with molecular docking, ADMET, QSAR, Bioactivity & toxicity risk studies and molecular finger print properties and found that in silico binding affinities were identified in good correlation with in vitro antioxidant activity and studied the structure activity relationship. The molecular docking study has disclosed strong hydrogen bonding interactions of title compounds with aspartic acid (ASP197) aminoacid residue of 2HCK, a complex enzyme of haematopoietic cell kinase and quercetin. Results of toxicology study evaluated for potential risks of compounds have revealed title compounds as safer drugs. In ultimate the study has established ligand's antioxidant potentiality as they effectively binds with ASP197 amino acid of Chain A hence confirms the inhibition of growth of reactive oxygen species in vivo. In addition, the title compounds have been identified as potential blood-brain barrier penetrable entities and efficient central nervous system (CNS) active neuro-protective antioxidant agents.
    Matched MeSH terms: Pyrimidines/chemistry
  4. Criofolinine and vernavosine, new pentacyclic indole alkaloids incorporating pyrroloazepine and pyridopyrimidine moieties derived from a common yohimbine precursor
    Nge CE, Gan CY, Lim KH, Ting KN, Low YY, Kam TS
    Org. Lett., 2014 Dec 19;16(24):6330-3.
    PMID: 25454201 DOI: 10.1021/ol503072g
    Two new indole alkaloids characterized by previously unencountered natural product skeletons, viz., criofolinine (1), incorporating a pyrroloazepine motif within a pentacyclic ring system, and vernavosine (2, isolated as its ethyl ether derivative 3, which on hydrolysis regenerated the putative precursor alkaloid 2), incorporating a pyridopyrimidine moiety embedded within a pentacyclic carbon framework, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined on the basis of NMR and MS analysis and confirmed by X-ray diffraction analysis.
    Matched MeSH terms: Pyrimidines/chemistry*
  5. Microwave assisted synthesis, cholinesterase enzymes inhibitory activities and molecular docking studies of new pyridopyrimidine derivatives
    Basiri A, Murugaiyah V, Osman H, Kumar RS, Kia Y, Ali MA
    Bioorg Med Chem, 2013 Jun 1;21(11):3022-31.
    PMID: 23602518 DOI: 10.1016/j.bmc.2013.03.058
    A series of hitherto unreported pyrido-pyrimidine-2-ones/pyrimidine-2-thiones were synthesized under microwave assisted solvent free reaction conditions in excellent yields and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activity. Among the pyridopyrimidine derivatives, 7e and 7l displayed 2.5- and 1.5-fold higher enzyme inhibitory activities against AChE as compared to standard drug, galanthamine, with IC50 of 0.80 and 1.37 μM, respectively. Interestingly, all the compounds except 6k, 7j and 7k displayed higher inhibitory potential against BChE enzyme in comparison to standard with IC50 ranging from 1.18 to 18.90 μM. Molecular modeling simulations of 7e and 7l was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) and human butyrylcholinesterase (hBChE) enzymes to disclose binding interaction and orientation of these molecule into the active site gorge of respective receptors.
    Matched MeSH terms: Pyrimidines/chemistry
  6. Development of solid dispersion systems of dapivirine to enhance its solubility
    Gorajana A, Ying CC, Shuang Y, Fong P, Tan Z, Gupta J, et al.
    Curr Drug Deliv, 2013 Jun;10(3):309-16.
    PMID: 23360246
    Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powder X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drug-excipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug.
    Matched MeSH terms: Pyrimidines/chemistry*
  7. Rapid determination of sildenafil and its analogues in dietary supplements using gas chromatography-triple quadrupole mass spectrometry
    Mokhtar SU, Chin ST, Kee CL, Low MY, Drummer OH, Marriott PJ
    J Pharm Biomed Anal, 2016 Mar 20;121:188-196.
    PMID: 26808068 DOI: 10.1016/j.jpba.2016.01.034
    Application of gas chromatography-triple quadrupole mass spectrometry for identification, confirmation and quantification of 6 phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, dimethylsildenafil, homosildenafil, thiosildenafil, thiodimethylsildenafil and thiohomosildenafil) in dietary supplements was investigated. The MS was operated in multiple reaction monitoring mode, for better sensitivity and selectivity. In this manner, the method is adequate to reduce background noise with less interference from co-eluting compounds in the samples. Two different ionisation techniques, electron ionisation (EI) and chemical ionisation (CI), were studied and compared. The chromatographic separation was performed on a short 10 m non-polar capillary column without any derivatisation step. This permitted fast analysis for all analogues with retention time less than 11 min, for both techniques. Use of backflushing can aid method retention time reduction and improves column maintenance. Evaluation of method validation included limit of detection (LOD), lower limit of quantitation (LLOQ), linearity, precision and recovery were performed for both EI and CI techniques. The LOD obtained varied from 0.03 to 1.50 μg/g and the LLOQ ranged from 0.10 to 5.00 μg/g. Good calibration linearity was obtained for all analogues for both techniques, with correlation coefficients (r(2)) higher than 0.99. Mean recoveries of all analogues using CI show higher values (83.4-108.8%) than that of EI (61.9-91.1%). The intra- and inter-assay precisions were evaluated for all analogues at spiked concentration of 10 μg/g and the relative standard deviation was less than 15% for both methods. These methods were then successfully applied to dietary supplement samples without prior derivatisation, confirming that the samples were adulterated with sildenafil and/or its analogues.
    Matched MeSH terms: Pyrimidines/chemistry
  8. Fulltext Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities
    Ouyang Y, Yang H, Zhang P, Wang Y, Kaur S, Zhu X, et al.
    Molecules, 2017 Sep 22;22(10).
    PMID: 28937657 DOI: 10.3390/molecules22101592
    Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level. In the current study, we designed and synthesized a series of mt-DHFR inhibitors that contain a 2,4-diaminopyrimidine core with side chains to occupy the glycerol binding site with proper hydrophilicity for cell entry, and tested their anti-tubercular activity against Mtb H37Ra. Among them, compound 16l showed a good anti-TB activity (MIC = 6.25 μg/mL) with a significant selectivity against vero cells. In the molecular simulations performed to understand the binding poses of the compounds, it was noticed that only side chains of a certain size can occupy the glycerol binding site. In summary, the novel synthesized compounds with appropriate side chains, hydrophobicity and selectivity could be important lead compounds for future optimization towards the development of future anti-TB drugs that can be used as monotherapy or in combination with other anti-TB drugs or antibiotics. These compounds can also provide much information for further studies on mt-DHFR. However, the enzyme target of the compounds still needs to be confirmed by pure mt-DHFR binding assays.
    Matched MeSH terms: Pyrimidines/chemistry*
  9. Cholinesterase inhibitory activity versus aromatic core multiplicity: a facile green synthesis and molecular docking study of novel piperidone embedded thiazolopyrimidines
    Basiri A, Murugaiyah V, Osman H, Kumar RS, Kia Y, Hooda A, et al.
    Bioorg Med Chem, 2014 Jan 15;22(2):906-16.
    PMID: 24369842 DOI: 10.1016/j.bmc.2013.11.020
    Novel thiazolopyrimidine derivatives have been synthesized via microwave assisted, domino cascade methodology in ionic liquid and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Among the newly synthesized compounds 6d, 6a, 6e and 6b displayed higher AChE inhibitory activity than standard drug, galanthamine, with IC50 values of 0.53, 1.47, 1.62 and 2.05μM, respectively. Interestingly, all the compounds except for 6m-r and 6x displayed higher BChE inhibitory potentials than galanthamine with IC50 values ranging from 1.09 to 18.56μM. Molecular docking simulations for 6d possessing the most potent AChE and BChE inhibitory activities, disclosed its binding interactions at the active site gorge of AChE and BChE enzymes.
    Matched MeSH terms: Pyrimidines/chemistry
  10. Identification of thioketone analogues of sildenfil using gas chromatography-mass spectrometry
    Man CN, Noor NM, Lajis R
    J Chromatogr A, 2011 Sep 28;1218(39):7055-60.
    PMID: 21872876 DOI: 10.1016/j.chroma.2011.08.037
    Sildenafil analogues have been found adulterated in herbal preparations and food products that claim to have natural aphrodisiacs. In this study, a gas chromatography-mass spectrometry (GC-MS) assay was developed for the screening and identification of thioketone analogues of sildenafil. Thiopyrazolopyrimidine, a precursor or a cleavage product of thioketone analogue, exhibited characteristic fragment ions of m/z 328 and m/z 299 was found to be the best marker to screen the presence of general thioketone analogues. Identification by GC-MS assay was rapid and specific as all the studied thioketones showed characteristic mass fragmentations including their intact molecular ions. The developed GC-MS assay had successfully identified thiosildenafil, thiohomosildenafil and thiodimethylsildenafil in herbal preparation and food products.
    Matched MeSH terms: Pyrimidines/chemistry*
  11. Design, synthesis, in vitro Evaluation and docking studies on dihydropyrimidine-based urease inhibitors
    Iftikhar F, Ali Y, Ahmad Kiani F, Fahad Hassan S, Fatima T, Khan A, et al.
    Bioorg Chem, 2017 10;74:53-65.
    PMID: 28753459 DOI: 10.1016/j.bioorg.2017.07.003
    In our previous report, we have identified 3,4-dihydropyrimidine scaffold as promising class of urease inhibitor in a structure based virtual screen (SBVS) experiment. In present study, we attempted to optimize the scaffold by varying C-5 substituent. The elongation of the C-5 chain was achieved by the reaction of C-5 ester with hydrazine leading to C-5 carbohydrazides which were further used as building blocks for the synthesis of fifteen new compounds having diverse moieties. A significantly higher in vitro urease inhibitory activity with IC50 values in submicromolar range was observed for semithiocarbazide derivatives (4a-c, 0.58-0.79µM) and isatin Schiff base derivative 5a (0.23µM). Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its key amino acid residues. The overall results of urease inhibition have shown that these compounds can be further optimized and developed as lead urease inhibitors.
    Matched MeSH terms: Pyrimidines/chemistry
  12. Synthesis and evaluation of chalcone analogues based pyrimidines as angiotensin converting enzyme inhibitors
    Bukhari SN, Butt AM, Amjad MW, Ahmad W, Shah VH, Trivedi AR
    Pak J Biol Sci, 2013 Nov 01;16(21):1368-72.
    PMID: 24511749
    Hypertension is a widespread and frequently progressive ailment that imparts a foremost threat for cardiovascular and renal disorders. Mammoth efforts are needed for the synthesis of innovative antihypertensive agents to combat this lethal disease. Chalcones have shown antihypertensive activity through inhibition of Angiotensin Converting Enzyme (ACE). Hence, a series of chalcone analogues is synthesized and used as precursor for the synthesis of novel series of pyrimidines. Precursor chalcones were prepared by reacting aldehydes and ketones in presence of sodium hydroxide followed by synthesis of corresponding pyrimidines by reaction with urea in presence of potassium hydroxide. Both groups were then evaluated for their effects on ACE. The results depicted that pyrimidines were more active than chalcones with methoxy (C5 and P5) substitution showing best results to inhibit ACE. Given that chalcone analogues and pyrimidines show a potential as the angiotensin converting enzyme inhibitors.
    Matched MeSH terms: Pyrimidines/chemistry*
  13. Synthesis, antibacterial activity and cytotoxicity of new fused pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-c][1,2,4]triazine derivatives from new 5-aminopyrazoles
    Al-Adiwish WM, Tahir MI, Siti-Noor-Adnalizawati A, Hashim SF, Ibrahim N, Yaacob WA
    Eur J Med Chem, 2013 Jun;64:464-76.
    PMID: 23669354 DOI: 10.1016/j.ejmech.2013.04.029
    New 5-aminopyrazoles 2a-c were prepared in high yields from the reaction of known α,α-dicyanoketene-N,S-acetals 1a-c with hydrazine hydrate under reflux in ethanol. These compounds were utilized as intermediates to synthesize pyrazolo[1,5-a]-pyrimidines 3a-c, 4a-d, 5a-c, and 6a-c, as well as pyrazolo[5,1-c][1,2,4]triazines 7a-c and 8a-c, by the reaction of 2-[bis(methylthio)methylene]malononitrile, α,α-dicyanoketene-N,S-acetals 1a-b, acetylacetone, acetoacetanilide as well as acetylacetone, and malononitrile, respectively. Furthermore, cyclization of 2a-c with pentan-2,5-dione yielded the corresponding 5-pyrrolylpyrazoles 9a-c. Moreover, fusion of 2a-c with acetic anhydride resulted in the corresponding 1-acetyl-1H-pyrazoles 10a-c. The antibacterial activity and cytotoxicity against Vero cells of several selected compounds are also reported.
    Matched MeSH terms: Pyrimidines/chemistry
  14. Synthesis, in vitro biological activities and in silico study of dihydropyrimidines derivatives
    Barakat A, Islam MS, Al-Majid AM, Ghabbour HA, Fun HK, Javed K, et al.
    Bioorg Med Chem, 2015 Oct 15;23(20):6740-8.
    PMID: 26381063 DOI: 10.1016/j.bmc.2015.09.001
    We describe here the synthesis of dihydropyrimidines derivatives 3a-p, and evaluation of their α-glucosidase enzyme inhibition activities. Compounds 3b (IC50=62.4±1.5 μM), 3c (IC50=25.3±1.26 μM), 3d (IC50=12.4±0.15 μM), 3e (IC50=22.9±0.25 μM), 3g (IC50=23.8±0.17 μM), 3h (IC50=163.3±5.1 μM), 3i (IC50=30.6±0.6 μM), 3m (IC50=26.4±0.34 μM), and 3o (IC50=136.1±6.63 μM) were found to be potent α-glucosidase inhibitors in comparison to the standard drug acarbose (IC50=840±1.73 μM). The compounds were also evaluated for their in vitro cytotoxic activity against PC-3, HeLa, and MCF-3 cancer cell lines, and 3T3 mouse fibroblast cell line. All compounds were found to be non cytotoxic, except compounds 3f and 3m (IC50=17.79±0.66-20.44±0.30 μM), which showed a weak cytotoxic activity against the HeLa, and 3T3 cell lines. In molecular docking simulation study, all the compounds were docked into the active site of the predicted homology model of α-glucosidase enzyme. From the docking result, it was observed that most of the synthesized compounds showed interaction through carbonyl oxygen atom and polar phenyl ring with active site residues of the enzyme.
    Matched MeSH terms: Pyrimidines/chemistry
  15. Method development and validation for the simultaneous determination of imatinib mesylate and N-desmethyl imatinib using rapid resolution high performance liquid chromatography coupled with UV-detection
    Tan KL, Ankathil R, Gan SH
    J Chromatogr B Analyt Technol Biomed Life Sci, 2011 Nov 15;879(30):3583-91.
    PMID: 22000961 DOI: 10.1016/j.jchromb.2011.09.048
    We developed a simple and sensitive method for the simultaneous detection of imatinib mesylate (IM) and its active metabolite, N-desmethyl imatinib (M1), in human serum samples. Separation was successfully achieved using an Agilent(®) ZORBAX Eclipse plus C(18) reversed phase column (50 mm × 2.1 mm, i.d.; 1.8 μm) under isocratic mobile phase conditions consisting of acetonitrile: 0.02 M potassium dihydrogen phosphate with 0.2% triethylamine at pH 3 (25:75, v/v) and ultra-violet detection was achieved at 235 nm. Extraction of the target compounds was completed using 100% cold acetonitrile. Good linearities (r(2)>0.99) for both IM and M1 were achieved for the concentration ranges of 50-1800 ng/mL and 50-360 ng/mL, respectively. The detection limits were 20 ng/mL and 10 ng/mL for M1 and IM, respectively. The intra- and inter-day precisions were less than 1% with percent recoveries of more than 90%. The method was successfully applied to calculate the pharmacokinetic parameters of chronic myeloid leukemia patients receiving imatinib. The method is suitable to be routinely applied for determination of IM and M1 in serum.
    Matched MeSH terms: Pyrimidines/chemistry
  16. Lack of hepato- and nephrotoxicity induced by antifungal drug voriconazole in laboratory rats
    Somchit N, Chung JH, Yaacob A, Ahmad Z, Zakaria ZA, Kadir AA
    Drug Chem Toxicol, 2012 Jul;35(3):304-9.
    PMID: 22288423 DOI: 10.3109/01480545.2011.614619
    Voriconazole is a new, potent broad-spectrum triazole systemic antifungal drug, a second-generation azole antifungal that is increasing in popularity, especially for the treatment of invasive aspergillosis and fluconazole-resistant invasive Candida infections. However, it is also known to induce hepatotoxicity clinically. The aim of this study was to investigate the hepatotoxicity and nephrotoxicity potential of voriconazole in vivo in rats. Forty rats were treated intraperitoneally with voriconazole as single (0, 10, l00, and 200 mg/kg) or repeated (0, 10, 50, and l00 mg/kg per day for 14 days) doses. Venous blood was collected for the repeated-dose group on days 1 and 14. Rats were sacrificed 24 hours after the last dose. Body weight, liver weight, and kidney weight of rats were recorded. Livers and kidneys samples were taken for histological and transmission electron microscopy (TEM) analysis. Results revealed that voriconazole had no effects on serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphotase, gamma glutamyl transpeptidase, blood urea nitrogen, and creatinine for both the single- and repeated-dose groups. However, histologically, in the repeated 50- and 100-mg/kg voriconazole-treated rats, mild focal inflammation was observed. Under TEM, only small changes in the 100 mg/kg/day group were revealed. These results collectively demonstrated that voriconazole did not induce significant hepatotoxicity and nephrotoxicity, even at very high doses.
    Matched MeSH terms: Pyrimidines/chemistry
  17. New pyrimidine-benzoxazole/benzimidazole hybrids: Synthesis, antioxidant, cytotoxic activity, in vitro cyclooxygenase and phospholipase A2-V inhibition
    Abdelgawad MA, Bakr RB, Ahmad W, Al-Sanea MM, Elshemy HAH
    Bioorg Chem, 2019 11;92:103218.
    PMID: 31536956 DOI: 10.1016/j.bioorg.2019.103218
    To enhance the cytotoxicity of benzimidazole and/or benzoxazole core, the benzimidazole/benzoxazole azo-pyrimidine were synthesized through diazo-coupling of 3-aminophenybenzimidazole (6a) or 3-aminophenylbenzoxazole (6b) with diethyl malonate. The new azo-molanates 6a&b mixed with urea in sodium ethoxide to afford the benzimidazolo/benzoxazolopyrimidine 7a&b. The structure elucidation of new synthesized targets was proved using spectroscopic techniques NMR, IR and elemental analysis. The cytoxicity screening had been carried out against five cancer cell lines: prostate cancer (PC-3), lung cancer (A-549), breast cancer (MCF-7), pancreas cancer (PaCa-2) and colon cancer (HT-29). Furthermore, the antioxidant activity, phospholipase A2-V and cyclooxygenases inhibitory activities of the target compounds 7a&b were evaluated and the new compounds showed potent activity (cytotoxicity IC50 range from 4.3 to 9.2 µm, antioxidant activity from 40% to 80%, COXs or LOX inhibitory activity from 1.92 µM to 8.21 µM). The docking of 7a&b was made to confirm the mechanism of action.
    Matched MeSH terms: Pyrimidines/chemistry
  18. Design, Synthesis and Therapeutic Potential of Some 6, 6'-(1,4- phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine)analogues
    Kumar S, Narasimhan B, Lim SM, Ramasamy K, Mani V, Shah SAA
    Mini Rev Med Chem, 2019;19(7):609-621.
    PMID: 30526456 DOI: 10.2174/1389557519666181210162413
    BACKGROUND: A series of 6, 6'-(1,4-phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine) derivatives has been synthesized by Claisen-Schmidt condensation and its chemical structures was confirmed by FT-IR, 1H/13C-NMR spectral and elemental analyses. The molecular docking study was carried out to find the interaction between active bis-pyrimidine compounds with CDK-8 protein. The in vitro antimicrobial potential of the synthesized compounds was determined against Gram-positive and Gram-negative bacterial species as well fungal species by tube dilution technique. Antimicrobial results indicated that compound 11y was found to be most potent one against E. coli (MICec = 0.67 µmol/mL) and C. albicans (MICca = 0.17 µmol/mL) and its activity was comparable to norfloxacin (MIC = 0.47 µmol/mL) and fluconazole (MIC = 0.50 µmol/mL), respectively.

    CONCLUSION: Anticancer screening of the synthesized compounds using Sulforhodamine B (SRB) assay demonstrated that compounds 2y (IC50 = 0.01 µmol/mL) and 4y (IC50= 0.02 µmol/mL) have high antiproliferative potential against human colorectal carcinoma cancer cell line than the reference drug (5- fluorouracil) and these compounds also showed best dock score with better potency within the ATP binding pocket and may also be used lead for rational drug designing.

    Matched MeSH terms: Pyrimidines/chemistry*
  19. Synthesis, in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one schiff bases
    Narender M, Jaswanth S B, Umasankar K, Malathi J, Raghuram Reddy A, Umadevi KR, et al.
    Bioorg Med Chem Lett, 2016 Feb 01;26(3):836-840.
    PMID: 26755393 DOI: 10.1016/j.bmcl.2015.12.083
    Development of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) has been considered as major health burden, globally. In order to develop novel, potential molecules against drug resistant TB, twenty two (22) new 3-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7-benzyl-2-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were designed and synthesized by using appropriate synthetic protocols. Pantothenate synthetase (PS) was considered as the target for the molecular docking studies and evaluated the binding pattern at active site, as PS plays a significant role in the biosynthesis of pantothenate in Mycobacterium tuberculosis (MTB). The preliminary in vitro antibacterial screening of test compounds was carried out against two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria. The antimycobacterial screening was performed against MTB H37Rv and an isoniazid-resistant clinical isolate of MTB. The compounds 6b, 6c, 6d, 6k, 7b, 7c, 7d and 7k exhibited promising antibacterial activity MIC in the range of 15-73 μM against all bacterial strains used and compounds 6d and 7b showed antimycobacterial activity (IC50 <340 μM in LRP assay) and (MIC <9 μM in broth microdilution method).
    Matched MeSH terms: Pyrimidines/chemistry*
  20. Fulltext Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment
    Shao YM, Ma X, Paira P, Tan A, Herr DR, Lim KL, et al.
    PLoS One, 2018;13(1):e0188212.
    PMID: 29304113 DOI: 10.1371/journal.pone.0188212
    Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM).
    Matched MeSH terms: Pyrimidines/chemistry
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