- Synthesis, characterization, crystal structure and cytotoxicity of 2,4-bis(selenomethyl)quinazoline
-
Organoselenium compounds have already been reported to be good anticarcinogenic candidates. A new selenoquinazoline derivative, 2,4-bis(selenomethyl)quinazoline (compound 1), has been synthesized, spectroscopically characterized and its crystal structure has been studied. An intermolecular coupling between C2 and H′ 5 in the Heteronuclear Multiple Bond Correlation (HMBC) experiment has been observed. Assuming that the headto- tail overlap of parallel molecules (as identified by X-ray diffraction) remains in solution to give bimolecular entities, the p-p interaction enables heteronuclear coupling between the former atoms with a three-bond distance [C2...(φ-φ)..C′ 5-H′ 5]. The crystal structure of compound 1 has been solved by X-ray diffraction. It crystallizes in triclinic system, space group P-1. Unit cell parameters are a = 7.4969(7) A , b = 8.7008(8) A , c = 10.1666(9) A , α = 110.215(2)-, β = 90.354(2)-, c = 115.017(1)-. Linear chains in crystals of compound 1 are generated by C-H...Se and Se..Se bonds between molecules. Furthermore, head-to-tail overlap of parallel molecules, in which p-p interactions can occur, is observed. Compound 1 exhibited a cytotoxic effect in all of the evaluated tumoral cell lines and showed a higher cytotoxic effect in colon and breast cancer cell lines than etoposide, which was used as a reference compound.
- Plano, Daniel,Ibanez, Elena,Palop, Juan Antonio,Sanmartin, Carmen
-
-
Read Online
- From triazolophthalazines to triazoloquinazolines: A bioisosterism-guided approach toward the identification of novel PCAF inhibitors with potential anticancer activity
-
Inhibition of PCAF bromodomain has been validated as a promising strategy for the treatment of cancer. In this study, we report the bioisosteric modification of the first reported potent PCAF bromodomain inhibitor, L-45 to its triazoloquinazoline bioisosteres. Accordingly, three new series of triazoloquinazoline derivatives were designed, synthesized, and assessed for their anticancer activity against a panel of four human cancer cells. Three derivatives demonstrated comparable cytotoxic activity with the reference drug doxorubicin. Among them, compound 22 showed the most potent activity with IC50 values of 15.07, 9.86, 5.75, and 10.79 μM against Hep-G2, MCF-7, PC3, and HCT-116 respectively. Also, compound 24 exhibited remarkable cytotoxicity effects against the selected cancer cell lines with IC50 values of 20.49, 12.56, 17.18, and 11.50 μM. Compounds 22 and 25 were the most potent PCAF inhibitors (IC50, 2.88 and 3.19 μM, respectively) compared with bromosporine (IC50, 2.10 μM). Follow up apoptosis induction and cell cycle analysis studies revealed that the bioisostere 22 could induce apoptotic cell death and arrest the cell cycle of PC3 at the G2/M phase. The in silico molecular docking studies were additionally performed to rationalize the PCAF inhibitory effects of new triazoloquinazoline bioisosteres.
- El-Shershaby, Mohamed H.,Ghiaty, Adel,Bayoumi, Ashraf H.,Al-Karmalawy, Ahmed A.,Husseiny, Ebtehal M.,El-Zoghbi, Mona S.,Abulkhair, Hamada S.
-
-
Read Online
- Design, synthesis and anti-influenza A virus activity of novel 2,4-disubstituted quinazoline derivatives
-
Four 2,4-disubstituted quinazoline series containing various amide moieties were designed and synthesized as new anti-influenza A virus agents using the strategies of bio-isosterism and scaffold hopping. Many of them exhibit potent in vitro anti-influenza A virus activity and low cytotoxicity (CC50: >100 μM). Particularly, compounds 10a5 and 17a show better activity (IC50: 3.70–4.19 μM) and higher selective index (SI: >27.03, >23.87, respectively) against influenza A/WSN/33 virus (H1N1), opening a new direction for quinazoline derivatives in anti-influenza A virus field.
- Cen, Shan,Wang, Juxian,Wang, Minghua,Wang, Yucheng,Wang, Yujia,Zhang, Guoning,Zhu, Mei
-
-
Read Online
- Design and discovery of new 1,2,4-triazolo[4,3-c]quinazolines as potential DNA intercalators and topoisomerase II inhibitors
-
A new series of 1,2,4-triazolo[4,3-c]quinazoline derivatives was designed and synthesized as Topo II inhibitors and DNA intercalators. The cytotoxic effect of the new members was evaluated in vitro against a group of cancer cell lines including HCT-116, HepG-2, and MCF-7. Compounds 14c, 14d, 14e, 14e, 15b, 18b, 18c, and 19b exhibited the highest activities with IC50 values ranging from 5.22 to 24.24 μM. Furthermore, Topo II inhibitory activities and DNA intercalating affinities of the most promising candidates were evaluated as a possible mechanism for the antiproliferative effect. The results of the Topo II inhibition and DNA binding tests were coherent with that of in vitro cytotoxicity. Additionally, the most promising compound 18c was analyzed in HepG-2 cells for its apoptotic effect and cell cycle arrest. It was found that 18c can induce apoptosis and arrest the cell cycle at the G2–M phase. Finally, molecular docking studies were carried out for the designed compounds against the crystal structure of the DNA?Topo II complex as a potential target to explore their binding modes. On the basis of these studies, it was hypothesized that the DNA binding and/or Topo II inhibition would participate in the noted cytotoxicity of the synthesized compounds.
- Alesawy, Mohamed S.,Al-Karmalawy, Ahmed A.,Elkaeed, Eslam B.,Alswah, Mohamed,Belal, Ahmed,Taghour, Mohammed S.,Eissa, Ibrahim H.
-
-
Read Online
- Synthesis and antimicrobial activity of bis(azolyl)quinazoline-2,4-diamines
-
Abstract: Some new bis(azolylamino)- and bis(azolylmethylamino)quinazolines were prepared from 2,4-dichloroquinazoline and azolyl amines under ultrasonication and tested for their antimicrobial activity. The chloro-, bromo-, and nitro-substituted bis(thia
- Rekha, Tamatam,Durgamma, Suram,Padmaja, Adivireddy,Padmavathi, Venkatapuram
-
-
Read Online
- Discovery of new coumarin substituted quinazolines as potential bioactive agents
-
In view of the biological importance of some important pharmacophores such as quinazoline, coumarin, and benzothiazole, we frame these moieties in a single molecular scaffold to be screened in vitro for their antimicrobial activity. The newly synthesized analogs have been examined for their in vitro biological efficacy against two Gram-positive bacteria, three Gram-negative bacteria, two fungi, and for antimycobacterial activity against M. tuberculosis H37Rv. The bioassay results revealed that the majority of final analogs exhibited potential bio efficacies with the remarkable level of MICs comparable to control drugs. The new synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR, and MS analysis.
- Patel, Amit B.,Raval, Rinku M.
-
-
Read Online
- [1,2,4]Triazolo[4,3-c]quinazoline and bis([1,2,4]triazolo)[4,3-a:4′,3′-c]quinazoline derived DNA intercalators: Design, synthesis, in silico ADMET profile, molecular docking and anti-proliferative evaluation studies
-
In view of their DNA intercalation activities as anticancer agents, novel fifteen [1,2,4]triazolo[4,3-c]quinazoline and bis([1,2,4]triazolo)[4,3-a:4′,3′-c]quinazoline derivatives have been designed, synthesized and evaluated against HepG2 and HCT-116. The molecular design was performed to investigate the binding mode of the proposed compounds with DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling studies. HCT-116 was found to be more sensitive cell lines to the influence of the new derivatives. In particular, compounds 16, 18, 11 and 5 were found to be the most potent derivatives with IC50 = 3.61, 6.72, 7.16 and 5.18 μM respectively against HepG2 cell line. Also, compounds 16, 18, 11 and 5 displayed IC50 = 2.85, 3.82, 4.97 and 6.40 μM respectively against HCT-116 cell line. These derivatives displayed higher activities than doxorubicin, (IC50 = 7.94 and 8.07 μM respectively) against the two HepG2 and HCT-116 cell lines. The most active anti-proliferative derivatives 5, 6, 10, 11, 13, 16, 18, 19 and 20 were further evaluated for their DNA-binding affinity which revealed the ability of these compounds to intercalate DNA. The tested compounds displayed very strong to moderate DNA-binding affinities. Compounds 16 and 18 potently intercalate DNA at IC50 values of 26.03 and 28.37 μM respectively which were lower than IC50 of Doxorubicin (IC50 = 31.27). This finding indicated that these derivatives exhibited higher DNA binding activities than Doxorubicin. Also, compounds 11 and 5 displayed very strong DNA binding at IC50 = 30.84 and 33.56 μM respectively, which were nearly equipotent to that of doxorubicin. Moreover, most of our derivatives exhibited good ADMET profile.
- El-Adl, Khaled,Ibrahim, Mohamed-Kamal,Alesawy, Mohammed S.I.,Eissa, Ibrahim H.
-
-
Read Online
- Design, synthesis, in silico ADMET, docking, and antiproliferative evaluations of [1,2,4]triazolo[4,3-c]quinazolines as classical DNA intercalators
-
Eleven novel [1,2,4]triazolo[4,3-c]quinazolines were designed, synthesized, and evaluated against HepG2 and HCT-116 cells. The molecular design was performed to investigate the binding mode of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling. HCT-116 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compounds 6f and 6e were found to be the most potent derivatives over all the tested compounds against the two HepG2 and HCT116 cancer cell lines, with IC50 = 23.44 ± 2.9, 12.63 ± 1.2, and 25.80 ± 2.1, and 14.32 ± 1.5 μM, respectively. Although compounds 6f and 6e displayed less activity than doxorubicin (IC50 = 7.94 ± 0.6 and 8.07 ± 0.8 μM, respectively), both could be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. The most active derivatives 6a, 6c, 6e, and 6f were evaluated for their DNA-binding activities. Compound 6f displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC50 value (54.08 μM). Compounds 6a, 6c, and 6e exhibited good DNA-binding affinities, with IC50 values of 79.35, 84.08, and 59.35 μM, respectively. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles were calculated for the four most active compounds in comparison to doxorubicin as a reference drug. Our derivatives 6a, 6c, 6e, and 6f displayed very good in-silico-predicted ADMET profiles. Doxorubicin violates three of Lipinski's rules, our derivatives 6a, 6c, 6e, and 6f do not violate any rule.
- Alesawy, Mohamed S.,Eissa, Ibrahim H.,El-Adl, Khaled,Ibrahim, Mohamed-Kamal
-
-
- Design, synthesis and evaluation of anti-proliferative activity of 2-aryl-4-aminoquinazoline derivatives as EGFR inhibitors
-
A class of 2-aryl-4-aminoquinazoline derivatives (7a-7j, 8a-8h, 9a-9h and 10a-10k) were designed, synthesized and evaluated as EGFR inhibitors. The anti-proliferative activity of compounds in vitro showed that compound 9e was considered to be a promising derivative. Compared with the lead compound Angew2017-7634-1, 9e exhibited excellent inhibitory activity against A549, NCI-H460 and H1975 cell lines, with IC50 values of 14.33 ± 1.16 μM, 17.81 ± 1.25 μM and 13.41 ± 1.14 μM, respectively. Moreover, 9e could effectively inhibit against Ba/F3-EGFRDel19/T790M/C797S cell lines. In the kinase experiment, the most promising compound 9e exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M, with an IC50 value of 0.74 μM. Further activity studies showed that 9e could not only induce remarkable cell-apoptosis of A549, but also block A549 cell lines in S-phase in a concentration-dependent manner. Furthermore, molecular docking study revealed the binding mode of 9e. All in all, we analyzed the structure–activity relationship of the target compounds, and explored their mechanism of action.
- Zhou, Zhihui,He, Jie,Yang, Feiyi,Pan, Qingshan,Yang, Zunhua,Zheng, Pengwu,Xu, Shan,Zhu, Wufu
-
-
- Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
-
A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.
- Zhang, Zixue,Zhang, Qingwei,Zhang, Hao,Jiao, Minru,Guo, Zheng,Peng, Xinyan,Fu, Lei,Li, Jianqi
-
-
- 1,2,4-Triazolo[4,3-c]quinazolines: a bioisosterism-guided approach towards the development of novel PCAF inhibitors with potential anticancer activity
-
Targeting PCAF with small inhibitor molecules has emerged as a potential therapeutic strategy for the treatment of cancer. Recently, L-45 was identified as a potent triazolophthalazine inhibitor of the PCAF bromodomain. Here, we report the bioisosteric modification of the triazolophthalazine ring system of L-45 to its bioisosteric triazoloquinazoline while maintaining other essential structural fragments for effective binding with the binding site of PCAF. Consequently, a set of sixteen triazoloquinazoline derivatives were designed, synthesized, and investigated for their anticancer activity against four human cancer cell lines. Five derivatives demonstrated comparable cytotoxic activity with that of doxorubicin as a reference anticancer drug. Among them, compound23showed the most potent activity with IC50values of 6.12, 4.08, 7.17, and 6.42 μM against HePG2, MCF-7, PC3, and HCT-116, respectively. Also, compound21exhibited comparable cytotoxic effects with that of doxorubicin against the selected cancer cell lines with IC50values in the range of 7.41-9.58 μM. Molecular docking and pharmacokinetic studies were additionally performed to rationalize the binding affinities of the newly designed triazoloquinazolines toward the active site of histone acetyltransferase PCAF and to evaluate the druggability of new compounds. The results of these studies suggested that PCAF binding could be the mechanism of action of these derivatives.
- El-Shershaby, Mohamed H.,Ghiaty, Adel,Bayoumi, Ashraf H.,Ahmed, Hany E. A.,El-Zoghbi, Mona S.,El-Adl, Khaled,Abulkhair, Hamada S.
-
p. 11136 - 11152
(2021/07/06)
-
- A Diverse Range of Hemozoin Inhibiting Scaffolds Act on Plasmodium falciparum as Heme Complexes
-
A diverse series of hemozoin-inhibiting quinolines, benzamides, triarylimidazoles, quinazolines, benzimidazoles, benzoxazoles, and benzothiazoles have been found to lead to exchangeable heme levels in cultured Plasmodium falciparum (NF54) that ranged over an order of magnitude at the IC50. Surprisingly, less active compounds often exhibited higher levels of exchangeable heme than more active ones. Quantities of intracellular inhibitor measured using the inoculum effect exhibited a linear correlation with exchangeable heme, suggesting formation of heme-inhibitor complexes in the parasite. In an effort to confirm this, the presence of a Br atom in one of the benzimidazole derivatives was exploited to image its distribution in the parasite using electron spectroscopic imaging of Br, an element not naturally abundant in cells. This showed that the compound colocalized with iron, consistent with its presence as a heme complex. Direct evidence for this complex was then obtained using confocal Raman microscopy. Exchangeable heme and inhibitor were found to increase with decreased rate of killing, suggesting that slow-acting compounds have more time to build up exchangeable heme complexes. Lastly, some but not all compounds evidently cause pro-oxidant effects because their activity could be attenuated with N-acetylcysteine and potentiated with t-butyl hydroperoxide. Collectively, these findings suggest that hemozoin inhibitors act as complexes with free heme, each with its own unique activity.
- Openshaw, Roxanne,Maepa, Keletso,Benjamin, Stefan J.,Wainwright, Lauren,Combrinck, Jill M.,Hunter, Roger,Egan, Timothy J.
-
p. 362 - 376
(2021/02/01)
-
- Synthesis and enzymological characterization of some 2-(Substituted-phenylamino)quinazolin-4(3h)-one derivatives as potent α-glucosidase inhibitors in vitro
-
Background: α-Glucosidase is an important hydrolytic enzyme playing a vital role in digestion of carbohydrates. It catalyzes the final step of carbohydrates digestion in biological systems and converts unabsorbed oligosaccharides and disaccharides into monosaccharides, thus resulting in hyperglycemia for diabetic patients. In this respect, it has been considered as a therapeutic target for the treatment of type 2 diabetes since the enzyme inhibition delays carbohydrate digestion and monosaccharide absorption and subsequently reduces postprandial plasma glucose levels. Objective: In this study, fourteen 2-(substitutedphenylamino)quinazolin-4(3H)-one derivatives were synthesized and evaluated for their α-glucosidase inhibitory activities. Methods: The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The biological activity and enzyme inhibition kinetic studies were performed by spectro-photometrical method using microplate reader. Physicochemical and drug-likeness properties of selected compounds were predicted by in silico method. Results: The biological activity results revealed that all of the synthesized compounds showed more potent α-glucosidase inhibitory activity in the range of IC50 = 58 ± 2-375 ± 15 μM when compared to the standard drug acarbose (IC50 = 892 ± 7 μM). Among the tested compounds, compound 12 bearing chlorine substituent at ortho position on N-phenyl ring displayed the highest inhibition with an IC50 value of 58 ± 2 μM against α-glucosidase. Furthermore, the enzyme inhibition kinetic study of the most active compound 12 indicated that the compound inhibited the α-glucosidase enzyme as uncompetitive with a Ki value of 63.46 μM. On the other hand, physicochemical and drug-likeness properties of selected compounds were predicted by in silico method. According to the results, it can be speculated that synthesized 2-phenylaminoquinazolin-4(3H)-one derivatives possessed favorable drug-likeness and pharmacokinetic profiles. Conclusion: In the light of results, 2-(substitutedphenylamino)quinazolin-4(3H)-one derivatives may serve as lead compounds to develop novel α-glucosidase inhibitors.
- Ayan, Emre Kadir,Soyer, Zeynep,Uysal, ?irin
-
p. 723 - 732
(2021/10/02)
-
- Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors
-
The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described N4-benzyl-N2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (Ki = 1.4 μM). Here, we describe the synthesis and biological evaluation of 22 analogs of 1a, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations. During the optimization of 1a, structure-based design and prediction of physicochemical properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.
- Barbosa Da Silva, Elany,Rocha, Débora A.,Fortes, Isadora S.,Yang, Wenqian,Monti, Ludovica,Siqueira-Neto, Jair L.,Caffrey, Conor R.,McKerrow, James,Andrade, Saulo F.,Ferreira, Rafaela S.
-
p. 13054 - 13071
(2021/09/13)
-
- Design, synthesis and in vitro anti-influenza A virus evaluation of novel quinazoline derivatives containing S-acetamide and NH-acetamide moieties at C-4
-
It is an urgent need to develop more effective anti-influenza agents due to the emergence of highly pathogenic and drug-resistant influenza viruses. Herein, a series of 2,4-disubstituted quinazoline derivatives were designed, synthesized and their antiviral activities against influenza A virus were evaluated. Nine compounds (10a2, 16a, 16e, 16i, 16j, 16n, 16o, 16p and 16r) showed potent activity against influenza A virus (IAV) with IC50 at the low-micromole level (1.29–9.04 μM). Particularly, 16e and 16r possess good anti-IAV activity (IC50: 1.29 μM and 3.43 μM, respectively) and acceptable cytotoxicity, and inhibit the transcription and replication of viral RNA. Together with reasonable PK profiles of 16e, these results suggest their promising potential as candidates for further investigation.
- Zhang, Guoning,Wang, Minghua,Zhao, Jianyuan,Wang, Yujia,Zhu, Mei,Wang, Juxian,Cen, Shan,Wang, Yucheng
-
-
- One-pot cascade ring enlargement of isatin-3-oximes to 2,4-dichloroquinazolines mediated by bis(trichloromethyl)carbonate and triarylphosphine oxide
-
An efficient and convenient one-pot cascade synthesis of 2,4-dichloroquinazolines directly from isatin-3-oximes with the addition of bis(trichloromethyl)carbonate and triarylphosphine oxide was developed, leading to substituted quinazolines in moderate to excellent yields. The efficiency of this transformation was demonstrated by compatibility with a range of functional groups. Thus, the method represents a convenient and practical strategy for the synthesis of substituted 2,4-dichloroquinazolines.
- Qin, Jinjing,Li, Zhenhua,Ma, Shengzhe,Ye, Lixian,Jin, Guoqiang,Su, Weike
-
supporting information
p. 1007 - 1012
(2020/07/10)
-
- Design, synthesis, and anticancer activities of sodium quinazolin-4-diselenide compounds
-
Substituted 4-chloroquinazoline reacted with sodium diselenide to give novel sodium quinazoline-4-diselenide compounds. The reaction provides an efficient and facile approach to the synthesis of sodium quinazoline-4-diselenide compounds. Structures of title compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. MTT assay was adopted to show anticancer activities of the compounds. Compounds 5a and 5h showed good activities against cancer-cell lines MDA-MB-435, MDA-MB-231, A549, SiHa, and HeLa. In addition, 5a exhibited quite good anticancer effects on relative above cell lines with 10μM concentration compared with oxaliplatin and gefitinib of the commercial anticancer drugs.
- Zhang, Yuchun,Niu, Pengpeng,Wen, Quanwu,Sun, Lin,Wang, Weili,Xu, Shengguang,Liu, Gang
-
p. 497 - 502
(2019/11/03)
-
- Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles
-
Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.
- Han, Sheng,Sang, Yali,Wu, Yan,Tao, Yuan,Pannecouque, Christophe,De Clercq, Erik,Zhuang, Chunlin,Chen, Fen-Er
-
-
- 2,4-DIAMINOQUINAZOLINE DERIVATIVES FOR INHIBITING ENDOPLASMIC RETICULUM (ER) STRESS
-
Novel 2,4-diaminoquinazoline derivatives are disclosed. The compounds can be used in treating diseases and conditions which are associated with abnormal cell function related to endoplasmic reticulum (ER) stress. For example, the compounds can be used as suppressors of ER stress-induced pancreatic β-cell dysfunction and death, for example in the treatment of diabetes.
- -
-
Paragraph 0099
(2019/02/24)
-
- Discovery of novel quinazolines as potential anti-tubulin agents occupying three zones of colchicine domain
-
A series of novel quinazolines as tubulin inhibitors occupying three zones of colchicine domain have been designed and synthesized inspired by the recently disclosed crystal structure of verubulin analogue 6 with tubulin. Among the newly synthesized compounds, 19c showed noteworthy potency against K562, HepG2, KB, HCT-8 and MDB-MB-231 cancer cells. In vitro microtubule polymerization assays identified 19c as a potent tubulin assembly inhibitor, the binding mode of which with tubulin was confirmed by molecular modeling studies to occupy three zones of tubulin domain. Furthermore, 19c disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis and depolarized mitochondria of K562 cells. 19c also reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 19c significantly and dose dependently inhibited tumor growth in H22 liver cancer xenograft mouse model. All these results suggested that 19c deserves further research as a novel and potential anti-tubulin agent for the treatment of cancers.
- Li, Wenlong,Yin, Ying,Shuai, Wen,Xu, Feijie,Yao, Hong,Liu, Jie,Cheng, Keguang,Xu, Jinyi,Zhu, Zheying,Xu, Shengtao
-
p. 380 - 390
(2018/11/10)
-
- COMPOUND FOR ORGANIC ELECTRONIC ELEMENT, ORGANIC ELECTRONIC ELEMENT USING SAME, AND ELECTRONIC DEVICE COMPRISING SAME
-
The present invention provides a novel compound capable of improving the light emitting efficiency, stability and life span of a device, and an organic electric element and an electronic device using the same.
- -
-
Paragraph 0255; 0258; 0259
(2018/09/23)
-
- COMPOUND FOR ORGANIC ELECTRIC ELEMENT, ORGANIC ELECTRIC ELEMENT COMPRISING THE SAME AND ELECTRONIC DEVICE THEREOF
-
The present invention provides the compound represented by Formula 1, and an organic electric element comprising a first electrode, a second electrode, and an organic material layer formed between the first electrode and the second electrode, wherein the organic material layer comprises the compound represented by Formula 1. The driving voltage of an organic electronic device can be lowered, and the luminous efficiency, color purity and life time of an organic electronic device can be improved by comprising the compound represented by Formula 1 in the organic material layer.
- -
-
Paragraph 0224; 0227; 0228
(2018/10/21)
-
- 4-AMINO-2-PYRIDO-BICYCLIC PYRIMIDINES AND USE THEREOF AS TOPOISOMERASE II INHIBITORS
-
The present invention concerns 4-amino-2-pyrido-bicyclic pyrimidines as type II topoisomerase inhibitors and use thereof as medicaments especially in the treatment of cancer. The invention also provides a method for the manufacture of 4- amino-2-pyrido bicyclic pyrimidines.
- -
-
Page/Page column 64-65
(2018/07/29)
-
- Pyrimidine derivatives, preparation method therefor and application of pyrimidine derivatives
-
The invention belongs to the field of drug synthesis and relates to novel pyrimidine derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, preparation methods of thenovel pyrimidine derivatives and the pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof and use of the novel pyrimidine derivatives and the pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of therapeutic agents, particularly PAK inhibitors. The derivatives disclosed by the invention are represented by a general formula (I) or (II), wherein each substituent is as defined in claims.
- -
-
Paragraph 0150; 0151; 0155; 0156; 0168; 0169
(2018/03/26)
-
- HEPARANASE INHIBITORS AND USE THEREOF
-
The invention relates to functionalized quinazoline compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds as heparanase inhibitors for the treatment of diseases or conditions related to heparanse activity.
- -
-
Paragraph 0143
(2018/07/05)
-
- COMPOUND FOR ORGANIC ELECTRIC ELEMENT, ORGANIC ELECTRIC ELEMENT COMPRISING THE SAME AND ELECTRONIC DEVICE THEREOF
-
The present invention provides: a compound having high light-emitting efficiency, having low driving voltage, and improving the lifespan of a device; an organic electric element using the same; and an electronic device thereof. The compound is represented by chemical formula 1. In the chemical formula 1, X is one of N-L^1-R^1 S, O, CR^aR^b; n and m are 0 or 1, and n+m is at least 1 (here, when n is 0, A is a single bond, and when m is 0, B is a single bond); A and B are independently one of a single bond, N-L^2-R^2, S, O, CR^cR^d; and Z^1 to Z^12 are independently CR^3, N, wherein at least one is N, and each CR^3 is independently the same or different when at least two of Z^1 to Z^12 are CR^3.(110) Substrate(120) Positive electrode(130) Hole injection layer(140) Hole transporting layer(141) Buffer layer(150) Light-emitting layer(151) Light-emitting assisting layer(160) Electron transfer layer(170) Electron injection layer(180) Negative electrodeCOPYRIGHT KIPO 2017
- -
-
Paragraph 0404; 0407-0408
(2018/02/03)
-
- COMPOUND FOR ORGANIC ELECTRIC ELEMENT, ORGANIC ELECTRIC ELEMENT COMPRISING THE SAME AND ELECTRONIC DEVICE THEREOF
-
The present invention refers to for high luminous efficiency, compounds capable of low driving voltage on the organic layer, the organic electric element and electronic device using the same number [...] substrate. (by machine translation)
- -
-
Paragraph 0514; 0517; 0518
(2018/02/03)
-
- Quinazoline, pyridopyrimidine or pyrimidopyrimidine derivative epidermal growth factor inhibitor and preparing method and application thereof
-
The invention discloses a selectivity inhibitor of a clinical mutant of EGFR protein tyrosine kinase. The selectivity inhibitor of the clinical mutant of EGFR protein tyrosine kinase has a structure which is shown in the formula (1) (The formula (1) is defined in the description), and is a double aromatic nucleus template compound containing quinazoline, pyridopyrimidine or pyrimidopyrimidine. The invention further discloses a preparing method of the compound and an application of the compound as the selectivity inhibitor of the clinical mutant of EGFR protein tyrosine kinase, especially an inhibiting effect of the compound in a T790M-variation EGFR and an application in treating diseases such as renal carcinoma, lung cancer, prostate gland cancer, pancreatic cancer, breast cancer and spongiocytoma, wherein the diseases are related to overexpression of the epidermal growth factor receptor EGFR.
- -
-
Paragraph 0036; 0038-0040
(2017/08/02)
-
- Synthesis and Antibacterial Activity of Sulfur-linked Bis and Tris Heterocycles
-
The bis and tris heterocycles-benzoxazolyl/benzothiazolyl/benzimidazolyl quinazolines linked by sulfur and/or nitrogen were prepared from 2,4-dichloroquinazoline and benzazolyl-2-thiol/benzazolyl-2-amine and studied their antibacterial activity. The nitro-substituted sulfur-linked bisbenzothiazolylquinazoline (12f), bisbenzimidazolylquinazoline (13f), and nitro-substituted sulfur and nitrogen-linked bisbenzothiazolylquinazoline (15f) were found to be potential antibacterial agents against Staphylococcus aureus.
- Mallikarjuna Reddy,Lavanya,Lakshmi Teja,Padmaja,Padmavathi
-
p. 2755 - 2766
(2017/09/26)
-
- Synthesis and structure-activity relationship of: N 4-benzylamine- N 2-isopropyl-quinazoline-2,4-diamines derivatives as potential antibacterial agents
-
A series of N4-benzylamine-N2-isopropyl-quinazoline-2,4-diamine derivatives has been synthesized and tested for antibacterial activity against five bacterial strains. Twelve different substituents on the N4-benzylamine group have been investigated along with replacement of the quinazoline core (with either a benzothiophene or regioisomeric pyridopyrimidine ring systems). In order to develop structure activity relationships, all derivatives were tested for their antibacterial activities against Escherichia coli and Staphylococcus aureus via Kirby-Bauer assays and minimum inhibitory concentration assays. Eight of the most potent compounds against S. aureus and E. coli were also screened against one strain of methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis and Salmonella typhimurium to further examine their antibacterial activities. Lead compound A5 showed good activities with MICs of 3.9 μg mL-1 against E. coli, S. aureus and S. epidermidis and 7.8 μg mL-1 against MRSA. Selected front runners were also screened for their DMPK properties in vitro to assess their potential for further development.
- Jiang, Zhengyun,Hong, W. David,Cui, Xiping,Gao, Hongcan,Wu, Panpan,Chen, Yingshan,Shen, Ding,Yang, Yang,Zhang, Bingjie,Taylor, Mark J.,Ward, Stephen A.,O'Neill, Paul M.,Zhao, Suqing,Zhang, Kun
-
p. 52227 - 52237
(2017/11/22)
-
- Synthesis method of 2,4-dichloro quinazoline
-
The invention discloses a synthesis method of 2,4-dichloro quinazoline. The synthesis method comprises the following steps: (1) mixing o-amino benzoyl chloride, carbon tetrachloride, an acid-binding agent, a catalyst, methyl carbamate and an organic solvent; (2) enabling reaction at 100 to 120 DEG C and 0.2 to 0.3 MPa for 5 to 7 hours; (3) heating to 200 to 230 DEG C, and continuously enabling reaction at 0.6 to 0.8 MPa for 20 to 25 hours; (4) filtering out insolubles, and extracting filtrate to obtain white solids. Compared with the prior art, the synthesis method disclosed by the invention has the advantages that the raw materials are readily available, the price is low, and the pollution is low; the reaction steps are relatively short, and one-step reaction is realized; furthermore, no high-toxicity and high-corrosiveness reactants are used, so that the operation is safe; the yield is high and can reach 97.0 percent or above.
- -
-
Paragraph 0013; 0014; 0015; 0016; 0017; 0018; 0019
(2017/05/23)
-
- BICYCLIC DERIVATIVE CONTAINING PYRIMIDINE RING, AND PREPARATION METHOD THEREFOR
-
The present invention provides: a bicyclic derivative comprising a pyrimidine ring, or a pharmaceutically acceptable salt thereof; a preparation method therefor, a pharmaceutical composition comprising the same; and a use therefor. According to the present invention, the bicyclic compound derivative comprising a pyrimidine ring, or a pharmaceutically acceptable salt thereof acts as a 5-HT4 receptor agonist, and thus can be usefully applied to the prevention or treatment of dysfunction in gastrointestinal motility, for example, gastrointestinal diseases such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, diabetic gastric atony and the like.
- -
-
Paragraph 0140; 0141
(2016/04/26)
-
- Design, synthesis and structure-activity relationships of novel diaryl urea derivatives as potential EGFR inhibitors
-
Two novel series of diaryl urea derivatives 5a-i and 13a-l were synthesized and evaluated for their cytotoxicity against H-460, HT-29, A549, and MDA-MB-231 cancer cell lines in vitro. Therein, 4-aminoquinazolinyl-diaryl urea derivatives 5a-i demonstrated significant activity, and seven of them are more active than sorafenib, with IC50 values ranging from 0.089 to 5.46 μM. Especially, compound 5a exhibited the most active potency both in cellular (IC50 = 0.15, 0.089, 0.36, and 0.75 μM, respectively) and enzymatic assay (IC50 = 56 nM against EGFR), representing a promising lead for further optimization.
- Jiang, Nan,Bu, Yanxin,Wang, Yu,Nie, Minhua,Zhang, Dajun,Zhai, Xin
-
-
- Synthesis and Biological Evaluation of N-[2-(4-Hydroxyphenylamino)-pyridin-3-yl]-4-methoxy-benzenesulfonamide (ABT-751) Tricyclic Analogues as Antimitotic and Antivascular Agents with Potent in Vivo Antitumor Activity
-
Benzopyridothiadiazepine (2a) and benzopyridooxathiazepine (2b) were modified to produce tricyclic quinazolinone 15-18 or benzothiadiazine 26-27 derivatives. These compounds were evaluated in cytotoxicity and tubulin inhibition assays and led to potent inhibitors of tubulin polymerization. N-[2(4-Methoxyphenyl)ethyl]-1,2-dihydro-pyrimidino[2,1-b]quinazolin-6-one (16a) exhibited the best in vitro cytotoxic activity (GI50 10-66.9 nM) against the NCI 60 human tumor cell line and significant potency against tubulin assembly (IC50 0.812 μM). In mechanism studies, 16a was shown to block cell cycle in G2/M phase and to disrupt microtubule formation and displayed good antivascular properties as inhibition of cell migration, invasion, and endothelial tube formation. Compound 16a was evaluated in C57BL/6 mouse melanoma B16F10 xenograft model to validate its antitumor activity, in comparison with reference ABT-751 (1). Compound 16a displayed strong in vivo antitumor and antivascular activities at a dose of 5 mg/kg without obvious toxicity, whereas 1 needed a 10-fold higher concentration to reach similar effects.
- Segaoula, Zacharie,Leclercq, Julien,Verones, Valérie,Flouquet, Nathalie,Lecoeur, Marie,Ach, Lionel,Renault, Nicolas,Barczyk, Amélie,Melnyk, Patricia,Berthelot, Pascal,Thuru, Xavier,Lebegue, Nicolas
-
p. 8422 - 8440
(2016/10/03)
-
- 2,4-disubstituted [...] compound, and its preparation, and pharmaceutical composition and use thereof
-
The invention discloses new 2,4-disubstituted quinazoline compounds and a preparation method, a medicinal composition and application thereof. The invention particularly relates to 2,4-disubstituted quinazoline compounds shown as a general formula I, medicinal salts thereof, precursors or derivatives thereof with the same biological function, a preparation method thereof, a composition containing one or more of the compounds, and application of the compounds in inhibiting activity of Pin1 enzyme, inhibiting activity of tumor growth and the like.
- -
-
Paragraph 0394; 0395
(2018/02/04)
-
- Discovery, Synthesis, and Evaluation of 2,4-Diaminoquinazolines as a Novel Class of Pancreatic β-Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress
-
Pancreatic insulin-producing β-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of β-cell dysfunction and death. In diabetes, a major cause for the decline in β-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of β-cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, 2,4-diaminoquinazoline compound 9c markedly protects β-cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 μM. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet β-cells. We showed that 9c protects β-cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis.
- Duan, Hongliang,Lee, Jae Wook,Moon, Sung Won,Arora, Daleep,Li, Yu,Lim, Hui-Ying,Wang, Weidong
-
p. 7783 - 7800
(2016/10/12)
-
- Convenient Synthesis of Novel Quinazoline Congeners via Copper Catalyzed C-N/C-S Coupling and Their Biological Evaluation
-
(Chemical Equation Presented) A library of novel quinazoline scaffolds endowed with semicarbazide/oxadiazole thiol motif synthesized via an efficient and sustainable copper catalyzed C-N/C-S coupling is reported, making the presented methodology extremely valuable from economic and environmental point of view. Among the all synthesized compounds screened for in vitro antibacterial, antifungal, and anti-TB activity, 7b, 7c, 7f, 9b, 9c, 9i, and 9j showed excellent inhibitory effect on particular strain of bacteria, fungi, and M. tuberculosis H37Rv as well. All the newly synthesized derivatives were well characterized by their IR, 1H NMR, 13C NMR, mass spectroscopy as well as elemental analysis.
- Lakum, Harshad P.,Shah, Dhruvin R.,Chikhalia, Kishor H.
-
p. 209 - 219
(2016/02/10)
-
- Design, synthesis and biological evaluation of 4-anilinoquinazoline derivatives as new c-myc G-quadruplex ligands
-
A series of 4-anilinoquinazoline derivatives were designed and synthesized as novel c-myc promoter G-quadruplex binding ligands. Subsequent biophysical and biochemical evaluation demonstrated that the introduction of aniline group at 4-position of quinazoline ring and two side chains with terminal amino group improved their binding affinity and stabilizing ability to G-quadruplex DNA. RT-PCR assay and Western blot showed that compound 7a could down-regulate transcription and expression of c-myc gene in Hela cells, which was consistent with the behavior of an effective G-quadruplex ligand targeting c-myc oncogene. More importantly, RTCA and colony formation assays indicated that 7a obviously inhibited Hela cells proliferation, without influence on normal primary cultured mouse mesangial cells. Flow cytometric assays suggested that 7a induced Hela cells to arrest in G0/G1 phase both in a time-dependent and dose-dependent manner.
- Jiang, Yin,Chen, Ai-Chun,Kuang, Guo-Tao,Wang, Shi-Ke,Ou, Tian-Miao,Tan, Jia-Heng,Li, Ding,Huang, Zhi-Shu
-
supporting information
p. 264 - 279
(2016/07/07)
-
- 2,4-quinazolinediamine derivatives, and preparation method and application thereof
-
The invention discloses 2,4-quinazolinediamine derivatives, and a preparation method and application thereof, belonging to the field of medicines and preparation and application thereof. The 2,4-quinazolinediamine derivatives comprises compounds as shown in a formula (I) which is described in the specification and a solvate, hydrate, tautomer and pharmaceutically acceptable salt thereof. Test results show that the 2,4-quinazolinediamine derivatives have strong Wolbachia resisting activity; and in the derivatives, 2-isopropylamido substitution has good effect, and compounds with better Wolbachia resisting activity can be obtained by changing a 4-amido group. The compounds have activity in resisting plasmodia, Wolbachia and bacteria.
- -
-
Paragraph 0135; 0138; 0139
(2017/04/18)
-
- Substituted piperazine compounds, application method and applications thereof
-
The invention discloses substituted piperazine compounds, an application method and applications thereof. Specifically, the invention relates to piperazine compounds and pharmaceutical compositions thereof for inhibiting reuptake of 5-hydroxytryptamine and/or stimulation of 5-HT1A acceptor. The invention also relates to a preparation method of the compounds and pharmaceutical compositions thereof, and an application of the compounds and pharmaceutical compositions thereof in the treatment of central nervous system dysfunction.
- -
-
Paragraph 0202; 0203; 0204; 0205
(2016/10/09)
-
- Cesium Carboxylate-Promoted Iridium Catalyzed C-H Amidation/Cyclization with 2,2,2-Trichloroethoxycarbonyl Azide
-
An Ir(III)-catalyzed direct C-H amidation/cyclization of benzamides using 2,2,2-trichloroethoxycarbonyl azide (TrocN3) as the aminocarbonyl source is reported. With the aid of cesium carboxylate, the reactions proceed efficiently and with high regioselectivity, producing various functionalized quinazoline-2,4(1H,3H)-diones, which are important building blocks and key synthetic intermediates for biologically and medicinally important compounds. During the reactions, two new C-N bonds were formed by breaking C-H and N-H bonds sequence.
- Zhang, Tao,Wang, Zhen,Hu, Xuejiao,Yu, Meng,Deng, Tianning,Li, Guigen,Lu, Hongjian
-
p. 4898 - 4905
(2016/07/06)
-
- Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists
-
Protease-activated receptor 2 (PAR2) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR2 may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4-amino-quinazoline derivatives as PAR2 antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8 μM. Binding modes of the newly identified PAR2 antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR2 homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) through the regulation of various intracellular signaling pathways involving nuclear factor-κB (NF-κB), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS-induced sepsis in mice. These results provide useful insights into the development of novel PAR2 antagonists with anti-inflammatory activity in vitro and in vivo.
- Cho, Nam-Chul,Cha, Ji Hyoun,Kim, Hyojin,Kwak, Jinsook,Kim, Dohee,Seo, Seung-Hwan,Shin, Ji-Sun,Kim, Taehun,Park, Ki Duk,Lee, Jiyoun,No, Kyoung Tai,Kim, Yun Kyung,Lee, Kyung-Tae,Pae, Ae Nim
-
p. 7717 - 7727
(2015/12/20)
-
- Discovery of novel potent and selective ligands for 5-HT2A receptor with quinazoline scaffold
-
Abstract A series of compounds with quinazoline scaffold were designed, synthesized and evaluated as novel potent 5-HT2A receptor ligands. N-(4-Chlorophenyl)-2-(piperazin-1-yl)quinazolin-4-amine (5o) has a Ki value of 14.04 ± 0.21 nM, with a selectivity more than 10,000 fold over 5-HT1A receptors (D1 and D2-like receptors). The functional assay showed that this compound is an antagonist to 5-HT2A receptor with an IC50 value of 1.66 μM.
- Deng, Xinxian,Guo, Lin,Xu, Lili,Zhen, Xuechu,Yu, Kunqian,Zhao, Weili,Fu, Wei
-
supporting information
p. 3970 - 3974
(2015/08/24)
-
- Synthesis and in vitro antimicrobial evaluation of piperazine substituted quinazoline-based thiourea/thiazolidinone/chalcone hybrids
-
In frames of the search for new biological entities to fight against recent drug-resistant microbial strains, we report a library of quinazoline-based thiourea/4-thiazolidinone/chalcone hybrids. The newly synthesized compounds were studied for efficacy against several bacteria (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Klebsiella pneumoniae) and fungi (Candida albicans and Aspergillus clavatus) using the broth dilution technique. From the biological evaluation, (E)-3-(3,4-dimethoxyphenyl)-1-(4-((4-(4-ethylpiperazin-1-yl)quinazolin-2-yl)amino)phenyl)prop-2-en-1-one was found to be the most active analogue (microbial inhibition concentration 3.12 μg/mL) to inhibit the bacterial growth. The rest of the compounds showed equipotent efficacy (3.12-12.5 μg/mL) as compared to the standard. Final compounds were characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis.
- Shah,Lakum,Chikhalia
-
p. 209 - 222
(2015/04/14)
-
- Synthesis and antimicrobial activity of amino linked heterocycles
-
Amino-linked benzoxazolyl/benzothiazolyl/benzimidazolyl quinazolines were prepared and their antimicrobial activity studied. The nitro-substituted benzothiazolyl quinazoline (8f) may be a potential antibacterial agent against Staphylococcus aureus and nitro-substituted benzimidazolyl quinazoline (9f) may be a potential antifungal agent against Aspergillus niger.
- Mallikarjuna Reddy, Lingaladinne,Dinneswara Reddy, Guda,Padmaja, Adivireddy,Padmavathi, Venkatapuram
-
-
- Discovery of 1-methyl-1 H-imidazole derivatives as potent Jak2 inhibitors
-
Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.
- Su, Qibin,Ioannidis, Stephanos,Chuaqui, Claudio,Almeida, Lynsie,Alimzhanov, Marat,Bebernitz, Geraldine,Bell, Kirsten,Block, Michael,Howard, Tina,Huang, Shan,Huszar, Dennis,Read, Jon A.,Rivard Costa, Caroline,Shi, Jie,Su, Mei,Ye, Minwei,Zinda, Michael
-
p. 144 - 158
(2014/02/14)
-
- Determinants of activity at human toll-like receptors 7 and 8: Quantitative Structure-Activity Relationship (QSAR) of diverse heterocyclic scaffolds
-
Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing heuristics to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity.
- Yoo, Euna,Salunke, Deepak B.,Sil, Diptesh,Guo, Xiaoqiang,Salyer, Alex C. D.,Hermanson, Alec R.,Kumar, Manoj,Malladi, Subbalakshmi S.,Balakrishna, Rajalakshmi,Thompson, Ward H.,Tanji, Hiromi,Ohto, Umeharu,Shimizu, Toshiyuki,David, Sunil A.
-
p. 7955 - 7970
(2014/12/10)
-
- Synthesis and in vitro antitumor evaluation of primary amine substituted quinazoline linked benzimidazole
-
By combining the structural features of quinazoline and benzimidazole, new hybrid regioisomeric molecules with substituted primary amines have been synthesized. Evaluation of these molecules over 60 cancer cell line panel has identified three molecules as most potent anticancer agents. Compound 10 showed ten and eleven folds more activity than respective quinazoline and benzimidazole class of compounds with GI50 value of 1.64 μM. Compound 11 (GI50 value of 0.81 μM) showed almost twenty and twenty-two fold more activity than quinazoline and benzimidazole analogue, respectively while compound 12 (GI50 value of 4.52 μM) has four fold more activity than quinazoline and benzimidazole analogue. In vitro evaluation of compound 11 exhibited remarkable anticancer activity towards colon cancer cell lines and prostate cancer cell lines at five dose concentrations with GI50 values of 0.34 and 0.31 μM, respectively.
- Paul, Kamaldeep,Sharma, Alka,Luxami, Vijay
-
supporting information
p. 624 - 629
(2014/01/23)
-
- Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors
-
Novel 2-chloro-4-anilino-quinazolines designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for inhibitory effects. EGFR and VEGFR-2 are validated targets in cancer therapy and combined inhibition might be synergistic for both antitumor activity and resistance prevention. The biological data obtained proved the potential of 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, highlighting compound 8o, which was approximately 7-fold more potent on VEGFR-2 and approximately 11-fold more potent on EGFR compared to the prototype 7. SAR and docking studies allowed the identification of pharmacophoric groups for both kinases and demonstrated the importance of a hydrogen bond donor at the para position of the aniline moiety for interaction with conserved Glu and Asp amino acids in EGFR and VEGFR-2 binding sites.
- Barbosa, Maria Letícia De Castro,Lima, Lídia Moreira,Tesch, Roberta,Sant'Anna, Carlos Mauricio R.,Totzke, Frank,Kubbutat, Michael H.G.,Sch?chtele, Christoph,Laufer, Stefan A.,Barreiro, Eliezer J.
-
-
- Antileishmanial activity of a series of N2, N 4-disubstituted quinazoline-2,4-diamines
-
A series of N2,N4-disubstituted quinazoline-2,4- diamines has been synthesized and tested against Leishmania donovani and L. amazonensis intracellular amastigotes. A structure-activity and structure-property relationship study was conducted in part using the Topliss operational scheme to identify new lead compounds. This study led to the identification of quinazolines with EC50 values in the single digit micromolar or high nanomolar range in addition to favorable physicochemical properties. Quinazoline 23 also displayed efficacy in a murine model of visceral leishmaniasis, reducing liver parasitemia by 37% when given by the intraperitoneal route at 15 mg kg-1 day-1 for 5 consecutive days. Their antileishmanial efficacy, ease of synthesis, and favorable physicochemical properties make the N2,N 4-disubstituted quinazoline-2,4-diamine compound series a suitable platform for future development of antileishmanial agents.
- Van Horn, Kurt S.,Zhu, Xiaohua,Pandharkar, Trupti,Yang, Sihyung,Vesely, Brian,Vanaerschot, Manu,Dujardin, Jean-Claude,Rijal, Suman,Kyle, Dennis E.,Wang, Michael Zhuo,Werbovetz, Karl A.,Manetsch, Roman
-
p. 5141 - 5156
(2014/07/08)
-
- Novel Hinge-Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure-Activity Relationship Study on Tofacitinib Bioisosteres
-
The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.
- Gehringer, Matthias,Forster, Michael,Pfaffenrot, Ellen,Bauer, Silke M.,Laufer, Stefan A.
-
supporting information
p. 2516 - 2527
(2015/08/24)
-