157864-32-9Relevant academic research and scientific papers
N4-benzyl-N2-phenylquinazoline-2,4-diamine compound presents antibacterial and antibiofilm effect against Staphylococcus aureus and Staphylococcus epidermidis
Reis, Sharon Vieira dos,Ribeiro, Nicole Sartori,Rocha, Débora Assump??o,Fortes, Isadora Serraglio,Trentin, Danielle da Silva,Andrade, Saulo Fernandes de,Macedo, Alexandre José
, p. 1372 - 1379 (2020)
Staphylococcus aureus and Staphylococcus epidermidis are the main agents involved with implant-related infections. Their ability to adhere to medical devices with subsequent biofilm formation is crucial to the development of these infections. Herein, we described the antibacterial and antibiofilm activities of a quinazoline-based compound, N4-benzyl-N2-phenylquinazoline-2,4-diamine, against both biofilm-forming pathogens. The minimum inhibitory concentrations (MIC) were determined as 25?μM for S.?aureus and 15?μM for S.?epidermidis. At sub-MIC concentrations (20?μM for S.?aureus and 10?μM for S.?epidermidis), the compound was able to inhibit biofilm formation without interfere with bacterial growth, confirmed by scanning electron microscopy. Moreover, surfaces coated with the quinazoline-based compound were able to prevent bacterial adherence. In addition, this compound presented no toxicity to human red blood cells at highest MIC 25?μM and in vivo toxicity assay using Galleria mellonella larvae resulted in 82% survival with a high dose of 500?mg/kg body weight. These features evidence quinazoline-based compound as interesting entities to promising applications in biomedical fields, such as antimicrobial and in anti-infective approaches.
Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity
Gilson, Paul R.,Tan, Cyrus,Jarman, Kate E.,Lowes, Kym N.,Curtis, Joan M.,Nguyen, William,Di Rago, Adrian E.,Bullen, Hayley E.,Prinz, Boris,Duffy, Sandra,Baell, Jonathan B.,Hutton, Craig A.,Jousset Subroux, Helene,Crabb, Brendan S.,Avery, Vicky M.,Cowman, Alan F.,Sleebs, Brad E.
, p. 1171 - 1188 (2017)
Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.
Modulation of peptidases by 2,4-diamine-quinazoline derivative induces cell death in the amitochondriate parasite Trichomonas vaginalis
Weber, Juliana Inês,Rigo, Graziela Vargas,Rocha, Débora Assump??o,Fortes, Isadora Serraglio,Seixas, Adriana,de Andrade, Saulo Fernandes,Tasca, Tiana
, (2021)
Trichomonas vaginalis is an amitochondriate protozoan and the agent of human trichomoniasis, the most prevalent non-viral sexually transmitted infection (STI) in the world. In this study we showed that 2,4-diamine-quinazoline derivative compound (PH100) kills T. vaginalis. PH100 showed activity against fresh clinical and American Type Culture Collection (ATCC) T. vaginalis isolates with no cytotoxicity against cells (HMVI, 3T3-C1 and VERO) and erythrocytes. In addition, PH100 showed synergistic action with metronidazole, indicating that these compounds act by different mechanisms. When investigating the mechanism of action of PH100 to ATCC 30236, apoptosis-like characteristics were observed, such as phosphatidylserine exposure, membrane alterations, and modulation of gene expression and activity of peptidases related to apoptosis. The apoptosis-like cell death features were not observed for the fresh clinical isolate treated with PH100 revealing distinct profiles. Our data revealed the heterogeneity among T. vaginalis isolates and contribute with the understanding of mechanisms of cell death in pathogenic eukaryotic organisms without mitochondria.
Discovery of EGF Receptor Inhibitors That Are Selective for the d746-750/T790M/C797S Mutant through Structure-Based de Novo Design
Park, Hwangseo,Jung, Hoi-Yun,Mah, Shinmee,Hong, Sungwoo
, p. 7634 - 7638 (2017)
Next-generation epidermal growth factor receptor (EGFR) inhibitors against the d746-750/T790M/C797S mutation were discovered through two-track virtual screening and de novo design. A number of nanomolar inhibitors were identified using 2-aryl-4-aminoquinazoline as the molecular core and the modified binding energy function involving a proper dehydration term, which provides important structural insight into the key principles for high inhibitory activities against the d746-750/T790M/C797S mutant. Furthermore, some of these EGFR inhibitors showed a greater than 1000-fold selectivity for the d746-750/T790M/C797S mutant over the wild type, as well as nanomolar activity against the mutant.
Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity
Ashton, Trent D.,Ngo, Anna,Favuzza, Paola,Bullen, Hayley E.,Gancheva, Maria R.,Romeo, Ornella,Parkyn Schneider, Molly,Nguyen, Nghi,Steel, Ryan W.J.,Duffy, Sandra,Lowes, Kym N.,Sabroux, Helene Jousset,Avery, Vicky M.,Boddey, Justin A.,Wilson, Danny W.,Cowman, Alan F.,Gilson, Paul R.,Sleebs, Brad E.
, (2021/10/26)
Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity. Structural modifications we have implemented improved LipE, aqueous solubility and in vitro metabolism while preserving fast acting P. falciparum asexual stage activity. The lead compounds demonstrated equipotent activity against P. knowlesi parasites and were not predisposed to resistance mechanisms of clinically used antimalarials. The optimized compounds exhibited modest activity against early-stage gametocytes, but no activity against pre-erythrocytic liver parasites. Confoundingly, the refined physicochemical properties installed in the compounds did not engender improved oral efficacy in a P. berghei mouse model of malaria compared to earlier studies on the 2-anilino quinazoline class. This study provides the framework for further development of this antimalarial class.
Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors
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)
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.
Synthesis, plasmodium falciparum inhibitory activity, cytotoxicity and solubility of n2,n4-disubstituted quinazoline-2,4-diamines
Pobsuk, Nattakarn,Suphakun, Praphasri,Hannongbua, Supa,Nantasenamat, Chanin,Choowongkomon, Kiattawee,Paul Gleeson
, p. 691 - 702 (2019/08/30)
Background: Despite the development of extensive control strategies and treatment options, approximately 200 million malaria cases, leading to approximately 450,000 deaths, were reported in 2015. Due to issue of disease resistance, additional drug development efforts are needed to produce new, more effective treatments. Quinazoline-2,4-diamines were identified as anti-parasitic compounds over three decades ago and have remained of interest to date in industry and academia. Objective: An anti-malarial SAR evaluation of previously unreported N2,N4-disubstituted quina-zoline-2,4-diamines have been undertaken in this study. We have synthesized and evaluated new derivatives against P. falciparum in our attempt to better characterize their biological activity and overall physical properties. Method: The synthesis of N2,N4-disubstituted quinazoline-2,4-diamines inhibitors is reported along with activities in a radioactive labeled hypoxanthine incorporation assay against the f Plasmodium falciparum (Pf.) K1 strain. In addition, cytotoxicity was determined in the A549 and Vero cell lines using an MTT based. The aqueous solubility of key compounds was assessed at pH 7.4 using a shake flask-based approach. Results: We identified compounds 1 and 6p as sub μM inhibitors of P. falciparum, having equivalent anti-malarial activity to Chloroquine. Compounds 1 and 6m are low μM inhibitors of P. falciparum with improved cytotoxicity profiles. Compound 6m displayed the best balance between P. falciparum Inhibitory activity (2 μM) and cytotoxicity, displaying >49 fold selectivity over A549 and Vero cell lines. Conclusion: Twenty one N2,N4-Disubstituted Quinazoline-2,4-diamines have been prepared in our group and characterized in terms of their antimalarial activity, cytotoxicity and physical properties. Compounds with good activity and reasonable selectivity over mammalian cell lines have been identified. SAR analyses suggest further exploration is are necessary to improve the balance of P. falciparum Inhibitory activity, cytotoxicity and solubility.
Design, synthesis and evaluation of N2,N4-diaminoquinazoline based inhibitors of phosphodiesterase type 5
Pobsuk, Nattakarn,Paracha, Tamkeen Urooj,Chaichamnong, Nattiya,Salaloy, Nattapas,Suphakun, Praphasri,Hannongbua, Supa,Choowongkomon, Kiattawee,Pekthong, Dumrongsak,Chootip, Krongkarn,Ingkaninan, Kornkanok,Gleeson, M. Paul
supporting information, p. 267 - 270 (2018/12/05)
We describe the design, synthesis and evaluation of a series of N2,N4-diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC50 = 0.072 ± 0.008 μM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC50s of 1.63 ± 0.72 μM and 2.28 ± 0.74 μM respectively.
Discovery, Synthesis, and Evaluation of 2,4-Diaminoquinazolines as a Novel Class of Pancreatic β-Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress
Duan, Hongliang,Lee, Jae Wook,Moon, Sung Won,Arora, Daleep,Li, Yu,Lim, Hui-Ying,Wang, Weidong
, p. 7783 - 7800 (2016/10/12)
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.
SAR refinement of antileishmanial N2,N4-disubstituted quinazoline-2,4-diamines Dedicated to the memory of Martin John Rogers for his sincere efforts to facilitate neglected disease research, particularly in the area of drug discovery and development
Zhu, Xiaohua,Van Horn, Kurt S.,Barber, Megan M.,Yang, Sihyung,Wang, Michael Zhuo,Manetsch, Roman,Werbovetz, Karl A.
, p. 5182 - 5189 (2015/03/18)
Visceral leishmaniasis is a neglected parasitic disease that has a high fatality rate in the absence of treatment. New drugs that are inexpensive, orally active, and effective could be useful tools in the fight against this disease. We previously showed that N2,N4-disubstituted quinazoline-2,4-diamines displayed low- to sub-micromolar potency against intracellular Leishmania, and lead compound N4-(furan-2-ylmethyl)-N2-isopropyl-7-methylquinazoline-2,4-diamine (4) exhibited modest efficacy in an acute murine model of visceral leishmaniasis. In the present work, thirty-one N2,N4-disubstituted quinazoline-2,4-diamines that had not previously been examined for their antileishmanial activity were evaluated for their potency and selectivity against Leishmania donovani, the causative parasite of visceral leishmaniasis. Quinazoline-2,4-diamines with aromatic substituents at both N2 and N4 exhibited potent in vitro antileishmanial activity but relatively low selectivity, while compounds substituted with small alkyl groups at either N2 or N4 generally showed lower antileishmanial potency but were less toxic to a murine macrophage cell line. Based on their in vitro antileishmanial potency, N4-benzyl-N2-(4-chlorobenzyl)quinazoline-2,4-diamine (15) and N2-benzyl-N4-isopropylquinazoline-2,4-diamine (40) were selected for in vivo evaluation of their pharmacokinetic and antileishmanial properties. While 15 displayed a longer plasma half-life and a greater area under the curve than 40, both compounds showed low efficacy in an acute murine visceral leishmaniasis model. Although the present study did not identify new quinazoline-2,4-diamines with promising in vivo efficacy, the reduced in vitro toxicity of derivatives bearing small alkyl groups at either N2 or N4 may provide clues for the design of safe and effective antileishmanial quinazolines.
