Adel S. El-Azab

Design, synthesis and biological evaluation of novel quinazoline derivatives as potential antitumor agents: Molecular docking study

Novel derivatives of quinazoline (1-27) have been synthesized and tested for their antitumor activity against three tumor cell lines among these cell lines the human breast carcinoma cell line (MCF-7) in which EGFR is highly expressed. All tested compounds showed potent and selective activity against breast cancer (MCF-7) with IC(50) range of 3.35-6.81 microg/ml. With regarding broad-spectrum activity compounds 5, 9, 15, 18 and 20 exploited potent antitumor against human liver cell line (HEPG2), human breast cell line (MCF-7) and human cervix cell line (HELA) with IC(50) range of 3.35-5.59 microg/ml. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.

Substituted quinazolines, part 3. Synthesis, in vitro antitumor activity and molecular modeling study of certain 2-thieno-4(3H)-quinazolinone analogs☆

The synthesis of some new 2-thieno-4(3H)-quinazolinone derivatives and their biological evaluation as antitumor agents using the National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Compounds 2-(2-thienylcarbonylamino)-5-iodo-N-(4-hydroxyphenyl)-benzamide (16), 2-(2-thieno)-6-iodo-3-phenylamino-3,4-dihydro-quina-zolin-4-one (26), and 2-(2-thieno)-4-[4-sulfonamidobenzylamino]-6-iodo-quinazoline (42), with GI(50) values of 12.7, 10.3, 16.9 microM, respectively, proved to be the most active members in this study, as compared to the known drug 5-FU. Conformational analysis of the most active molecules using molecular modeling and QSAR techniques enabled the understanding of the pharmacophoric requirements for 2-thieno-quinzolinone derivatives as antitumor agents. These three quinazolinone analogs (16, 26, 42) could be considered as useful templates for future development to obtain more potent antitumor agents.

Design, synthesis, and biological evaluation of substituted hydrazone and pyrazole derivatives as selective COX-2 inhibitors: Molecular docking study.

New arylhydrazone derivatives and a series of 1,5-diphenyl pyrazoles were designed and synthesized from 1-(4-chlorophenyl)-4,4,4-trifuorobutane-1,3-dione 1. The newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw oedema model. Moreover, they were tested for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Some of the new compounds (2f, 6a and 6d) showed a reasonable in vitro COX-2 inhibitory activity, with IC₅₀ value of 0.45 μM and selectivity index of 111.1. A virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Docking study of the synthesized compounds 2f, 6a and 6d into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones

A new series of 2,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 22, 33-37, 39-43, and 45 proved to be active DHFR inhibitors with IC(50) range of 0.4-1.0microM. Compound 18 showed broad-spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compounds 34 and 36 showed antitumor activity at GI(50) (MG-MID) concentrations of 11.2, and 24.2microM, respectively. Molecular modeling study including flexible alignment; electrostatic, hydrophobic mappings; and pharmacophore prediction were performed. A main featured pharmacophore model was developed which justifies the importance of the main pharmacophoric groups as well as of their relative distances. The substitution pattern and spatial considerations of the pi-systems in regard to the quinazoline nucleus proved critical for biological activity.

Synthesis, biological evaluation and molecular modeling study of pyrazole and pyrazoline derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Part 2

New pyrazole and pyrazoline derivatives have been synthesized and their ability to inhibit ovine COX-1/COX-2 isozymes was evaluated using in vitro cyclooxygenase (COX) inhibition assay. Among the tested compounds, N-((5-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)-3,5-bis(trifluoromethyl)aniline 8d exhibit optimal COX-2 inhibitory potency (IC(50)=0.26 lM) and selectivity (SI)=>192.3] comparable with reference drug celecoxib (IC(50) value of 0.28 lM and selectivity index of 178.57). Moreover, the anti-inflammatory activity of selected compounds, which are the most selective COX-2 inhibitors in the COX inhibition assay, was investigated in vivo using carrageenan-induced rat paw edema model. Molecular modeling was conducted to study the ability of the active compounds to bind into the active site of COX-2 which revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Synthesis and anticonvulsant evaluation of some new 2,3,8-trisubstituted-4(3H)-quinazoline derivatives.

A new series of 2,3,8-trisubstituted-4(3H)-quinazoline derivatives were synthesized, evaluated for their anticonvulsant activity against electrically (MES) and chemically (PTZ, picrotoxin and Strychnine) induced seizures and compared with the standard drugs methaqualone and sodium valproate. Compounds 3, 17 and 22 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.

Design and synthesis of novel 7-aminoquinazoline derivatives: Antitumor and anticonvulsant activities

A novel series of 7-substituted-4(3H)-quinazolinone were designed, synthesized and evaluated for their antitumor and anticonvulsant activity. Compound 7 revealed broad-spectrum antitumor effectiveness toward numerous cell lines that belong to different tumor subpanels, whereas compounds 9 and 18 possess selective activity toward leukemia cell lines. Additionally, compounds 3, 15, 16, 18, 19 and 20 showed advanced anticonvulsant activity as well as lower neurotoxicity than reference drugs. The achieved results proved that the distinctive compounds could be valuable as a model for future devise, acclimatization and investigation to construct more active analogues.

Synthesis, Analgesic and Anti-Inflammatory Evaluation of Some New 3H-Quinazolin-4-one Derivatives

In this study, we have synthesized a series of 3H‐quinazolin‐4‐ones in order to obtain new compounds with potential analgesic and anti‐inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti‐inflammatory activities by writhing and carrageenan‐induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12–14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose‐dependent anti‐inflammatory activity. The best dual analgesic / anti‐inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.

Synthesis of Some New Substituted 2-Mercaptoquinazoline Analogs as Potential Antimicrobial Agents

A new series of substituted 2-mercapto-3-(4-chlorophenyl)-6-iodo-3H-quinazolin-4-ones was prepared and screened for antimicrobial activity. Compounds 11, 13, 17, and 18 showed a remarkably broad spectrum of antimicrobial activity and could be useful as templates for further development through modification or derivatization to design more potent antimicrobial agents. A detailed synthesis of new 2-mercaptoquinazolinones and their antimicrobial screening are reported.

Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2

A group of cyclic imides (1-10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC50 range of 0.1-4.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 8a as a highly potent (IC50=0.1 μM), and an extremely selective [COX-2 (SI)>1000] comparable to celecoxib [COX-2 (SI)>384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=72.4 mg/kg) relative to diclofenac (ED50=114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO2NH2 group underwent H-bonding interaction with Gln(192)(2.95 Å), Phe(518)(2.82 Å) and Arg(513)(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.