Nagwa M. Abdel Gawad

Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4(3H)-ones and 4, 6- disubstituted- 1, 2, 3, 4-tetrahydroquinazolin-2H-ones.

The synthesis of some new 3-substituted quinazolin-4(3H)-ones and 3,4-dihydro-quinazolin-2(1H)-one derivatives and their biological evaluation as antitumor agents using the National Cancer Institute (NCI), disease oriented antitumor screening protocol are investigated. Compounds 2-[2-(4-chlorophenyl)-2-oxo-ethylthio]-3-(4-methoxyphenyl)quinazolin-4(3H)-one (3b), and 3-(4-chlorophenyl)-2-[2-(4-methoxyphenyl)-2-oxo-ethylthio]quinazolin-4(3H)-one (3d), are broad-spectrum antitumors showing effectiveness toward numerous cell lines that belong to different tumor subpanels, Compounds 3b, 3d are the most active members in this study. Those two quinazoline analogues could be considered as useful templates for future development to obtain more potent antitumor agent(s).

Synthesis, antitumor and antibacterial activities of some novel tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives.

Two series of new tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines namely 2,3-disubstituted derivatives 3a-z and 2,4-disubstituted ones 6a-c were prepared and tested for their antitumor and antibacterial activities. The structures of the prepared compounds were confirmed by spectral and elemental analyses. Compound 3z exhibited the highest antitumor activity against breast MCF-7 with IC50 = 0.19 μM compared to Doxorubicin (IC50 = 5.46 μM), while 3r was the most active one against liver HEPG-2 cancer cell line with IC50 = 1.29 μM as regard to Doxorubicin (IC50 = 7.36 μM). Concerning the antibacterial activity, compounds 3m and 3z exerted remarkable activity against the tested bacterial species compared to Ampicillin, whereas compound 6c showed good activity against only Gram positive species.

Synthesis of novel 1,3,4-trisubstituted pyrazoles as anti-inflammatory and analgesic agents.

Some novel 1,3,4-trisubstituted pyrazoles were synthesized and screened for their anti-inflammatory and analgesic activities as well as their ulcerogenic liability. They showed anti-inflammatory and analgesic activities with better GIT tolerance than the standard drug phenylbutazone. In addition, IC50 values for 5e and 8e were recorded. Compound 5e was found to be the most active one as anti-inflammatory and analgesic agent. On the other hand, COX-1/COX-2 isozyme selectivity was also done which showed equal inhibition to both isoforms.

New series of 6-substituted coumarin derivatives as effective factor Xa inhibitors: Synthesis, in vivo antithrombotic evaluation and molecular docking

Despite recent progress in antithrombotic therapy, theres still an unmet medical need for safe and orally available anticoagulants. Encouraged by the marked antithrombotic and anticoagulant activities of some coumarin derivatives, twenty-three new N-coumarinyl-4-amidinobenzamides 4a-f and 6-heterocycle substituted coumarin derivatives 5, 6a,b, 10a-e, 12a-e and 14a-d were synthesized and evaluated for their in vivo antithrombotic activity. The most active congeners were the unsubstituted amidine 4a (36.5 s), coumarinyl oxadiazole 5 (42.3 s), bis coumarinyl oxadiazole 6b (37.8 s) and coumarinyl pyrazole 10b (38.5 s) that presented prothrombin time (PT) values comparable to the reference drug warfarin (42.3 s). Furthermore, docking studies were undertaken to gain insight into the possible binding mode of these compounds with the coagulation factor Xa (FXa) binding site.

Design, synthesis, and anticonvulsant activity of novel quinazolinone analogues

A number of 2-substituted and 2,3-disubstituted quinazolinone analogues have been synthesized. Their structures have been elucidated on the basis of elemental analyses and spectroscopic studies (IR, 1H NMR, and MS). An evaluation of the anticonvulsant activity of the prepared compounds has indicated that some of them exhibit moderate to significant activity, compared to diazepam and phenobarbital standards.

Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines

A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84-702nM against hCA I, of 0.41-288nM against hCA II and of 5.6-29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines.

Synthesis of novel pyrazole and dihydropyrazoles derivatives as potential anti-inflammatory and analgesic agents

Novel dihydropyrazole 5–8, 10 and pyrazole derivatives 12, 14, 15, 17 were synthesized. The structures of the newly synthesized compounds were elucidated by spectral and elemental analyses. The anti-inflammatory activity of all new compounds was evaluated using the carrageenan-induced rat paw edema test using indomethacin and celecoxib as reference drugs. The most active derivatives as anti-inflammatory agents were accordingly tested for their analgesic activity using the p-benzoquinone-induced writhing method in mice and results revealed that these compounds had also good analgesic activity. The ulcerogenic liability of the selected compounds was also evaluated. Results showed that the selected derivatives had anti-inflammatory activity comparable to or slightly lower than the reference drugs, reaching about 82% inhibition with a considerable gastric safety profile.

Design and synthesis of some pyrazole derivatives of expected anti-inflammatory and analgesic activities

Design and synthesis of some pyrazole derivatives 4–11 of expected anti-inflammatory and analgesic activities. In addition, docking of the tested compounds into cyclooxygenase II using (MOE) was performed to rationalize the obtained biological results and their mechanism of action. The structures of the new compounds were elucidated by spectral and elemental analyses. All the newly synthesized compounds were evaluated for their anti-inflammatory activity using the carrageenan-induced rat paw edema method. Analgesic activity of the target compounds was measured using the p-benzoquinone writhing-induced method, and their ability to induce gastric toxicity was also evaluated. Results showed that the newly synthesized compounds exhibited weak to good activities compared to ibuprofen and celecoxib as reference drugs. Some compounds, such 4a and 11b exhibited significant anti-inflammatory activity with gastric ulcerogenic potential less than that of ibuprofen. Results of the analgesic activity showed that compounds possessing good anti-inflammatory activity showed also good analgesic. Substitution of pyrazole ring with at least one aryl moiety was found to be essential for anti-inflammatory and analgesic activities. Free NH (of pyrazole ring) and/or acidic group (COOH) will improve the anti-inflammatory activity.Graphical abstract

Benzoxepin derivatives: design, synthesis, and pharmacological evaluation with sedative–hypnotic effect

A series of novel benzoxepin-derived compounds were synthesized and evaluated for their sedative–hypnotic effect using Phenobarbital-induced sleep test in mice. Compound 6 in which the Phenobarbital moiety was incorporated into the benzoxepin nucleus was the most active one. Molecular modeling, including fitting to a 3D-pharmacophore model using Discovery Studio 2.1 programs into optimized benzodiazepine receptor (hypothesis) showed high fit values. The experimental studies for the in vivo sedative–hypnotic effect of compounds 2–6 and 11a–c were consistent with the molecular modeling.Graphical abstractA series of novel benzoxepin-derived compounds were synthesized and evaluated for their sedative–hypnotic effect using Phenobarbital-induced sleep test in mice. Compound 6 in which the Phenobarbital moiety was incorporated into the benzoxepin nucleus was the most active one.