157864-32-9Relevant articles and documents
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.
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.
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.
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.
