Fadi M. Awadallah

Synthesis and biological evaluation of novel coumarin-pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor agents.

Two groups of coumarin-pyrazoline hybrids were synthesized. The target compounds were obtained by cyclization of the coumarin chalcones with various substituted hydrazines to produce the corresponding pyrazolines through 1,4-addition on α,β-unsaturated carbonyl system. Selected compounds were investigated for their anticancer activity toward 60 cancer cell lines according to US NCI protocol where breast cancer MCF7 and colon cancer HCT-116 were the most susceptible to the influence of compounds 7d, 8c and 9c. Encouraged by this, all final compounds were screened against colorectal cell line HCT-116. The tested compounds exhibited high potency with IC(50) ranging from 0.01 μM to 2.8 μM. Moreover, compound 9c which possessed the highest cytotoxicity proved to have weak enzyme inhibitory activity against PI3K (p110α/p85α).

New quinazolinone-pyrimidine hybrids: synthesis, anti-inflammatory, and ulcerogenicity studies.

Two groups of hybrid compounds: the quinazolinone-dihydropyrimidines and quinazolinone-pyrimidines, were synthesized. The starting derivative 3 was reacted with chloroacetyl chloride to give intermediate 5 which was condensed with the 2-mercaptopyrimidines 4a-c affording compounds 6a-c. These latter compounds underwent hydrolysis and N-alkylation reactions to give the dihydropyrimidine derivatives 7a-c and 8a-f, respectively. The chloro derivatives 9a-c subsequently reacted with various anilines furnishing compounds 10a-i. The anti-inflammatory activity of the synthesized compounds were evaluated using the carrageenan-induced rat paw oedema model and ulcer indices for the most active compounds were calculated. Five compounds were found more active and less ulcerogenic than diclofenac particularly compound 10 g (IC(50) = 116.73 μmol/kg; ulcer index = 11.38). Compound 10 g was also 2-fold more selective inhibitor of COX-2 than COX-1.

Novel substituted and fused pyrrolizine derivatives: Synthesis, anti-inflammatory and ulcerogenecity studies

Synthesis of several substituted pyrrolizines 10a-f, 11a-f, 13a-c, pyrimidopyrrolizines 14a-c, 15a-c, and pyrrolizinopyrimidoisoindoles 12a-c was discussed. The starting compounds 6-amino-7-cyano-N-(4-(un)substitutedphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamides 9a-c were reacted with different aldehydes, acid chlorides, and acid anhydrides to give the target compounds. The structures of the new compounds were characterized by spectral and elemental analyses. All compounds were tested for their anti-inflammatory activity using the carrageenan-induced rat paw oedema model and exhibited weak to good activities compared to ketorolac as the reference drug. Also, analgesic activity of selected compounds, which are the most active in the anti-inflammatory screening, was measured using the acetic acid-induced writhing model; revealing activities comparable to or higher than ketorolac. Ulcer indices for the most active compounds were calculated and some compounds showed no or minimal ulcerogenic effect compared to ketorolac.

Synthesis and anticancer activity of some 8-substituted-7-methoxy-2H-chromen-2-one derivatives toward hepatocellular carcinoma HepG2 cells.

Based on the reported anticancer activity of coumarin and pyrazoline derivatives, the present investigation dealt with the design and synthesis of coumarin derivatives bearing diversely substituted pyrazoline moieties 7-10. The non-cyclic isosteres 11a-e of compounds 10a-e were synthesized for comparative reasons. The target compounds were synthesized from 8-acetyl-7-methoxycoumarin that underwent Claisen-Schmidt condensation with various aldehydes to give the chalcones 6a-e, followed by reaction with hydrazine hydrate, phenyl hydrazine or semicarbazide under the appropriate conditions. Cytotoxicity of the synthesized compounds was evaluated in vitro against liver HepG2 cell line. Compounds were active in the nanomolar range. The most active compounds were investigated for their telomerase inhibition and proapoptotic activities.

Synthesis, vasorelaxant activity, and molecular modeling study of some new phthalazine derivatives.

New phthalazine-based vasodilators were synthesized through the chloroacylation of the starting compound 1-hydrazinophthalazine 4 to give the two key intermediates 5 and 7. These intermediates were used to alkylate various cyclic amines to furnish the final compounds 6a-h and 8a-h. Compounds were tested for their vasorelaxant activities against nor-adrenaline-induced spasm on thoracic rat aorta rings and compared to the reference drug, prazosin. Seven compounds showed higher activity than prazosin, especially compound 8d having an IC(50)=0.10 mM. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α(1)-AR antagonists showed high docking score and fit values. Most vasodilation activities of tested compounds are consistent with their molecular modeling results.

Synthesis, carbonic anhydrase inhibition and cytotoxic activity of novel chromone-based sulfonamide derivatives

Four series of sulfonamides incorporating chromone moieties were synthesized and assessed for their cytotoxic activity against MCF-7 and A-549 cell lines, considering the fact that some of these tumors overexpress isoforms of carbonic anhydrase (CA, EC 4.2.1.1) which is inhibited by sulfonamides. Most new sulfonamides showed weak inhibitory activity against the offtarget, cytosolic isoforms hCA I, II but effectively inhibited the tumor-associated hCA IX and XII. The most active compounds featured a primary SO2NH2 group and were active in the low micromolar range against MCF-7 and A-549 cell lines. Compound 4a showed IC50 of 0.72 and 0.50 μM against MCF-7 and A-549 cell lines, respectively, and was further evaluated for its proapoptotic activity which proved enhanced in both tumor types.

Synthesis of some dihydropyrimidine-based compounds bearing pyrazoline moiety and evaluation of their antiproliferative activity

Two series of 2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-1-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitriles 5a-h and 4-(4-chlorophenyl)-2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitriles 6a-h were synthesized via a cyclocondensation reaction of the corresponding 2-hydrazinopyrimidines 3a,b with the appropriate 2-propen-1-ones 4a-h. The target compounds were screened for their antiproliferative activity against A 549 (lung), HT 29 (colon), MCF 7 and MDA-MB 231 (breast) cell lines. The two most susceptible cell lines were the colon (HT 29) and breast (MDA-MB 231). Generally, the 4-unsubstitutedphenylpyrimidine derivatives 5a-h were more active than their 4-chlorophenylpyrimidine analogs 6a-h. Compounds 5e and 5g, showed high activity against three of the cell lines. The most active compound 5c possessed IC₅₀ = 1.76 μM against A 549 cell line.

Synthesis, anti-inflammatory and ulcerogenicity studies of some substituted pyrimido[1,6-a]azepine derivatives.

New series of pyrimido[1,6-a]azepines were prepared through reaction of the key amino compound 4 with various reagents to give a variety of 3-N-substituted amino derivatives 5-13. The synthesized compounds included the Mannich bases 5a-c, the formimidic acid ester 6, the phenylformamidines 7a-c, the benzylidine amino derivatives 8a-c, the acetic acid derivatives 9, 10a-c and 11, the carbamoylformates 12a,b and the amides 13a,b. All compounds were screened for their anti-inflammatory activity using the carrageenan-induced paw oedema in rats using diclofenac sodium as reference drug. In addition, ulcer indices for the most active compounds were calculated. Compounds 3, 4, 8a,c, 11 and 12a,b showed activity similar to or higher than diclofenac sodium with no or minimal gastric ulceration. The most active compound with no ulcerogenic effect is the amino derivative 4 (IC 50 = 6.61 mmol/kg).

Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity

Efforts to develop new antitumor agents are now directed towards multitarget therapies that are believed to have high potency and low tendency to resistance compared to conventional drugs. Herein, we highlighted the synthesis and antitumor activity of five series of phthalazine-based compounds featuring a variety of bioactive chemical fragments at position 1 of the phthalazine nucleus. The antitumor activity of the target compounds was performed against fourteen cancer cell lines where all compounds were active in the nanomolar level. In addition, the mechanism of action of the target compounds was investigated through an enzymatic inhibitory assay against VEGFR-2 and EGFR kinases, revealing potent and preferential activity toward VEGFR-2. Binding mode of the most active compounds was studied using docking experiment.

Design and synthesis of potent 1,2,4-trisubstituted imidazolinone derivatives with dual p38αMAPK and ERK1/2 inhibitory activity

The synthesis of new 1,2,4-trisubstituted imidazolinone derivatives was described. The new compounds were designed as dual p38αMAPK and ERK1/2 inhibitors through hybridization of pharmacophoric elements associated with inhibition of these kinases. The kinase inhibition assay revealed excellent activity in the nanomolar range; especially compounds 6d and 7h which seemed promising candidates for such dual activity with IC50 values of 4.5 and 4.7 nM against p38αMAP, 25.0 and 24.0 nM against ERK1, and 3.2 and 3.5 nM against ERK2, respectively. These compounds were further tested for their antiproliferative activity against nine cancer cell lines, where they elicited high activity in the sub-micromolar range against breast, prostate and melanoma cells.