New oxadiazoles with selective-COX-2 and EGFR dual inhibitory activity: Design, synthesis, cytotoxicity evaluation and in silico studies.

Novel heterocyclic oxadiazoles viz. 2-subsituted-5-(4-pyridyl)-1,3,4-oxadiazoles, 2-subsituted-5-(3-pyridyl)-1,3,4-oxadiazoles and 2-subsituted-5-(phenyl or 4-chlorophenyl-1,3,4-oxadiazoles) were designed and synthesized as potential anticancer agents. In this investigation, all compounds were evaluated for their COX-1 and COX-2 inhibitory activity in vitro as new therapeutic approaches assumed cytotoxic effect associated with selective COX-2 inhibition. Results showed that most of the derivatives demonstrated inhibition towards both isoforms of COX comparable to the standard reference drugs indomethacin, diclofenac sodium and celecoxib. Then, nine selected compounds (IIId, VIb, VIIc, IX, XI, XIIa, XIVa, XVIb and XVIIIb) were subjected to cytotoxic screening against UO-31 renal cancer cell line using MTT assay. Compounds IIId, IX and XIIa displayed promising behavior by showing good anticancer activity. Moreover, kinase inhibitory assay against the tyrosine kinase EGFR was performed for the three compounds showing the highest cytotoxic activity. The tested compounds were potent against EGFR with the highest activity being observed for compound IX showing nearly double the potency of the reference drug Erlotinib. Moreover, molecular docking and molecular dynamics were performed for IIId, IX and XIIa against EGFR, in an attempt to elucidate a model for their binding at the molecular level, simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids. Finally, in silico pharmacokinetic profile predication was investigated for IIId, IX and XIIIa using SWISS/ADME to identify the most promising small-molecule cytotoxic agent on the basis of displaying the best drug-like properties. Results indicated that compound IX has a potential to serve as a lead compound for developing novel anticancer therapeutic agents.

Design, synthesis and biological evaluation of novel condensed pyrrolo[1,2-c]pyrimidines featuring morpholine moiety as PI3Kα inhibitors.

Four series of condensed pyrrolo[1,2-c]pyrimidines 6a-d, 8a-d, 10a,b and 12a-e designed as PI3Kα inhibitors were synthesized and evaluated for inhibitory activity and selectivity toward different PI3K isoforms. The tested compounds displayed PI3Kα kinase inhibitory activity at either low micromolar or nanomolar level. In particular, the morpholino-pyrimidopyrrolopyrimidinones 8a-d and morpholino-pyridopyrrolopyrimidine-2-carbonitriles 12a-e proved to be highly potent and selective PI3Kα inhibitors (IC50 = 0.1-7.7 nM). Moreover, the target compounds exhibited considerable cytotoxic activity against cervical cancer cell line HeLa that over-expresses p110α (0.21-1.99 µM). Molecular modeling simulation revealed that, the designed compounds docked well into p110α active site and their complexes are stabilized by a key H-bonding with the backbone amide of Val851 as well as other favorable hydrophobic and H-bond interactions with different amino acids within the enzyme active site.

Novel heterocyclic-fused pyrimidine derivatives: synthesis, molecular modeling and pharmacological screening.

Novel heterocyclic-fused pyrimidines viz pyrrolo[1,2-c]pyrimidines 4-8, pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 9-14, pyrimido[4',5':4,5]pyrimido[1,6-a]azepines 16-18, pyrrolo[1',2':1,6]pyrimido[4,5-d][1,3]thiazines 19a,b and 1,3-thiazino[4',5':4,5]pyrimido[1,6-a]-azepine 19c were designed and synthesized as potential anticancer agents. In this investigation all the newly synthesized compounds were subjected to cytotoxic screening against MCF-7 breast cancer cell line. Moreover, kinase inhibitory assay was done for compounds 5, 7, 9 and 18 against the non-receptor and receptor tyrosine kinases c-Src and VEGFR, respectively. The tested compounds were more potent against c-Src than VEGFR, and the highest activity was observed for 18 showing 81% c-Src activity inhibition. Finally, molecular docking was performed with c-Src and VEGFR in an attempt to simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids.

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, 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).

Synthesis and evaluation of some 1,2,3,4-tetrahydropyrimidine-2-thione and condensed pyrimidine derivatives as potential antihypertensive agents.

Some new tetrahydropyrimidine-2-thione, octahydroquinazoline-2-thione and thiazolo[3,2-a]pyrimidine derivatives have been synthesized and tested for their antihypertensive activity. Among them, compounds 1 and 2b can be considered more potent than the reference, nifedipine (CAS 21829-25-4), while compounds 3b and 10a are equipotent to it. In addition, compound 6 showed significant antihypertensive activity.