38283-38-4Relevant articles and documents
Synthesis, computational studies, tyrosinase inhibitory kinetics and antimelanogenic activity of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives
Rafiq, Muhammad,Nazir, Yasir,Ashraf, Zaman,Rafique, Hummera,Afzal, Samina,Mumtaz, Amara,Hassan, Mubashir,Ali, Anser,Afzal, Khurram,Yousuf, Muhammad Rizwan,Saleem, Muhammad,Kotwica-Mojzych, Katarzyna,Mojzych, Mariusz
, p. 1 - 11 (2019)
The over expression of melanogenic enzymes like tyrosinase caused many hyperpigmentaion disorders. The present work describes the synthesis of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives 3a–e and 5a–e as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives 3a–e and 5a–e was determined and it was found that derivative 5c possesses excellent activity with IC50 = 0.0089 μM compared to standard kojic acid (IC50 = 16.69 μM). The presence of hydroxyl groups at the ortho and the para position of cinnamic acid phenyl ring in compound 5c plays a vital role in tyrosinase inhibitory activity. The compound 5d also exhibited good activity (IC50 = 8.26 μM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound 5c is a competitive inhibitor while 5d is a mixed-type inhibitor. The mode of binding for compounds 5c and 5d with tyrosinase enzyme was also assessed and it was found that both derivatives irreversibly bind with target enzyme. The molecular docking and molecular dynamic simulation studies were also performed to find the position of attachment of synthesized compounds at tyrosinase enzyme (PDB ID 2Y9X). The results showed that all of the synthesized compounds bind well with the active binding sites and most potent derivative 5c formed stable complex with target protein. The cytotoxicity results showed that compound 5c is safe at a dose of 12 μg/mL against murine melanoma (B16F10) cells. The same dose of 5c was selected to determine antimelanogenic activity; the results showed that it produced antimelenogenic effects in murine melanoma (B16F10) cells. Based on our investigations, it was proposed that compound 5c may serve as a lead structure to design more potent antimelanogenic agents.
Phosphonate as a Stable Zinc-Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
Voos, Katrin,Sch?nauer, Esther,Alhayek, Alaa,Haupenthal, J?rg,Andreas, Anastasia,Müller, Rolf,Hartmann, Rolf W.,Brandstetter, Hans,Hirsch, Anna K. H.,Ducho, Christian
, p. 1257 - 1267 (2021/03/24)
Microbial infections are a significant threat to public health, and resistance is on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc-binding group (ZBG) variants of this thiol-derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development.
Design, synthesis, and anti-proliferative evaluation of new quinazolin-4(3H)-ones as potential VEGFR-2 inhibitors
El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Ayyad, Rezk R.,Mahdy, Hazem A.,Khalifa, Mohamed M.,Elnagar, Hamdy A.,Mehany, Ahmed B.M.,Metwaly, Ahmed M.,Elhendawy, Mostafa A.,Radwan, Mohamed M.,ElSohly, Mahmoud A.,Eissa, Ibrahim H.
, (2020/11/24)
Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Thus, nineteen new quinazoline-4(3H)-one derivatives were designed and synthesized. Preliminary cytotoxicity studies of the synthesized compounds were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Five compounds were found to have promising cytotoxic activities against all cell lines. Compound 16f, containing a 2-chloro-5-nitrophenyl group, has emerged as the most active member. It was approximately 4.39-, 5.73- and 1.96-fold more active than doxorubicin and 3.88-, 5.59- and 1.84-fold more active than sorafenib against HepG2, HCT-116 and MCF-7 cells, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities. The results of in vitro VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Molecular docking of these compounds into the kinase domain, moreover, supported the results.
Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities
Abdel Gawad, Nagwa M.,El Kerdawy, Ahmed M.,George, Riham F.,Georgey, Hanan H.,Mohamed, Abdalla R.
, (2021/01/04)
Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.
Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection
Li, Qi,Chen, Ying,Xing, Shuaishuai,Liao, Qinghong,Xiong, Baichen,Wang, Yuanyuan,Lu, Weixuan,He, Siyu,Feng, Feng,Liu, Wenyuan,Chen, Yao,Sun, Haopeng
, p. 6856 - 6876 (2021/05/29)
Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
New quinoxaline-2(1H)-ones as potential VEGFR-2 inhibitors: design, synthesis, molecular docking, ADMET profile and anti-proliferative evaluations
Abulkhair, Hamada S.,Eissa, Ibrahim H.,El-Adl, Khaled,ElSohly, Mahmoud A.,Elhendawy, Mostafa A.,Mehany, Ahmed. B. M.,Metwaly, Ahmed M.,Radwan, Mohamed M.,Sakr, Helmy M.,Yousef, Reda G.
, p. 16949 - 16964 (2021/09/27)
Eleven new quinoxaline derivatives were designed and synthesized as modified VEGFR-2 inhibitors of our previous work. The synthesized compounds were tested against three human cancer cell lines (HepG-2, MCF-7 and HCT-116). Compounds11g,11eand11cwere the most potent members against the tested cells. Compound11g(IC50= 4.50, 2.40, and 5.90 μM) was the most potent member compared to doxorubicin (IC50= 8.29, 9.65, and 7.68 μM) and sorafenib (IC50= 7.33, 9.41, and 7.23 μM) against HepG-2 and HCT-116, and MCF-7 cell lines, respectively. Compound11eshowed better anti-proliferative activities than doxorubicin and sorafenib with IC50values of 5.34, 4.19, and 6.06 μM, against HepG-2 and HCT-116 and MCF-7 cell lines, respectively. In addition, the most active anti-proliferative derivatives11c,11e,11f, and11gwere selected to evaluate their inhibitory activities against VEGFR-2. The tested compounds displayed good inhibitory activity with IC50values ranging from 0.75 to 1.36 μM. Among them, compound11gwas the most active member with an IC50value of 0.75 μM, compared to the reference drug; sorafenib (IC50= 1.29 μM). Moreover, docking studies revealed that the synthesized compounds have good binding patterns against the prospective molecular target; VEGFR-2. In addition,in silico, ADMET and toxicity studies showed a high level of drug likeness for the synthesized compounds.
Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers
Belal, Amany,Eissa, Ibrahim H.,El-Gamal, Kamal M. A.,El-Sharkawy, Abdou,Elhendawy, Mostafa A.,Elsohly, Mahmoud A.,Ibrahim, Mohammed K.,Mahdy, Hazem A.,Mehany, Ahmed B. M.,Metwaly, Ahmed M.,Radwan, Mohamed M.
, (2019/12/24)
Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26b, 29a, 29b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 μM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC50 value of 2.5 ± 0.04 μM, almost equal to that of sorafenib (IC50 = 2.4 ± 0.05 μM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities.
Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors
Khalifa, mohamed m.,Radwan, mohamed m.,Rashed, mahmoud,Sakr, Helmy,ayyad, Rezk R.,belal, amany,eissa, Ibrahim H.,el-Helby, abdel-Ghany a.,el-Sharkawy, abdou,elSohly, mahmoud a.,elhendawy, mostafa a.,mahdy, Hazem a.,metwaly, ahmed m.
, (2020/09/03)
Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 μM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 μM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.
Discovery of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors: Design, synthesis, and anti-proliferative evaluation
Eissa, Ibrahim H.,El-Helby, Abdel-Ghany A.,Mahdy, Hazem A.,Khalifa, Mohamed M.,Elnagar, Hamdy A.,Mehany, Ahmed B.M.,Metwaly, Ahmed M.,Elhendawy, Mostafa A.,Radwan, Mohamed M.,ElSohly, Mahmoud A.,El-Adl, Khaled
, (2020/11/02)
Sixteen novel quinazoline-based derivatives were designed and synthesized via modification of the VEGFR-2 reported inhibitor 7 in order to increase the binding affinity of the designed compounds to the receptor active site. The designed compounds were evaluated for their VEGFR-2 inhibitory effects. Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. The bioactivity of the new compounds was performed against HepG-2, MCF-7 and HCT-116 cell lines. Doxorubicin and sorafenib were used as positive controls. Compound 18d was observed to have promising cytotoxic activity (IC50 = 3.74 ± 0.14, 5.00 ± 0.20 and 6.77 ± 0.27 μM) in comparison to the reference drug doxorubicin (IC50 = 8.28, 9.63 and 7.67 μM) and sorafenib (IC50 = 7.31, 9.40 and 7.21 μM). The most active compounds were tested for their in vitro VEGFR-2 inhibitory activities. Results of VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Thus, compound 18d showed VEGFR-2 inhibitory activity (IC50 = 0.340 ± 0.04 μM) superior to that of the reference drug, sorafenib (IC50 = 0.588 ± 0.06 μM). Furthermore, docking study was performed in order to understand the binding pattern of the new compounds into VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key amino acids in the active site, Glu883 and Asp1044, as well as their hydrophobic interaction with the receptor hydrophobic pocket. Results of cytotoxic activities, in vitro VEGFR-2 inhibition together with docking study argument the advantages of the synthesized analogues as promising anti-angiogenic agents.
Selective cyclooxygenase inhibition and ulcerogenic liability of some newly prepared anti-inflammatory agents having thiazolo[4,5-d]pyrimidine scaffold
Bakr, Rania B.,Ghoneim, Amira A.,Azouz, Amany A.
, (2019/05/10)
Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l)were synthesized and their structures were elucidated by spectral and elemental analyses. All the novel derivatives were screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity, especially 1-(4-[7-(4-nitrophenyl)-5-thioxo-5,6-dihydro-3H-thiazolo[4,5-d]pyrimidin-2-ylideneamino]phenyl)ethanone (9g)was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. Furthermore, this derivative 9g recorded higher anti-inflammatory activity than celecoxib which showed 43%, 43% and 54% inhibition after 1, 3 and 5h, sequentially. Moreover, the target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2 (IC50 = 0.87–3.78 μM), in particular, the derivatives 9e (IC50 = 0.92 μM), 9g (IC50 = 0.87 μM)and 9k (IC50 = 1.02 μM)recorded higher COX-2 inhibitory effect than the selective COX-2 inhibitor drug celecoxib (IC50 = 1.11 μM). The in vivo potent compounds (9e, 9g and 9k)caused variable ulceration effect (ulcer index = 5–12.25)in comparison to that of celecoxib (ulcer index = 3). Molecular docking was performed to the most potent COX-2 inhibitors (9e, 9g and 9k)to explore the binding mode of these derivatives with Cyclooxygenase-2 enzyme.
