Synthesis of some tropane derivatives of anticipated activity on the reuptake of norepinephrine and/or serotonin.

A variety of tropane derivatives 14a-g were prepared via the reaction of the alcohol analogs 12a and 12b with substituted fluorobenzenes 13a-f. The prepared compounds were tested for their activity and selectivity toward the norepinephrine transporter (NET) and serotonin transporter (SERT) using yohimbine-induced mortality and 5-hydroxytryptophan-induced neurotoxicity in mice, respectively. All the tested compounds were found to be NE and 5-HT reuptake inhibitors except 14d which exhibited selective 5-HT reuptake inhibition activity.

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.

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.

New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines: synthesis, 2D-QSAR, anti-inflammatory, analgesic and ulcerogenicity studies.

New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines were synthesized. A series of ylidene carbohydrazides 14a-i, and hydrazonate 15, were obtained from the prepared 3-carbohydrazide derivative 13. Pyrazole derivatives 12, 16a,b, 18, 19, 20, were also prepared through different reactions. The anti-inflammatory and analgesic activities of all new compounds were evaluated and most of them exerted comparable activity to indomethacin and celecoxib. Ulcer indexes for the most active compounds were calculated and most of them showed less ulcerogenic effect than the reference drugs. The most potent anti-inflammatory compound 12 showed an IC(50) of 6.00 µmol/kg and low ulcer index. COX-1/COX-2 activity ratio of compounds 12 and 16b showed almost equal inhibitory effect on both isoenzymes. 2D-QSAR studies revealed good predictive and statistically significant QSAR models.

Synthesis, molecular docking study and antitumor activity of novel 2-phenylindole derivatives.

The starting material, 4-(1-indol-2-yl)phenol 1 was obtained via Fischer synthesis. Vilsmeir Haack(')s formylation of 1 gave the carboxaldehyde derivative 2 which was subjected to different reactions affording the 3-substituted compounds 3-10. Compound 1 reacted with halo esters to give 11 and 12a,b. The reaction of 12a with various amino derivatives gave compounds 13-16. The hydrazide derivative 15a reacted with 1,3-diketones, ethyl acetoacetate and aromatic carboxylic acid derivatives to give 17a,b, 18 and 19a-e, respectively. Antitumor activity of target compounds were tested against breast cancer cell lines (MCF-7) and (MDA-MB-231). The most potent compound was 3e with IC(50) = 1.60 nM against (MCF-7). Docking was performed on colchicine binding site of tubulin to study the binding mode of the designed compounds.

Synthesis, analgesic and anti-inflammatory activities evaluation of some bi-, tri- and tetracyclic condensed pyrimidines.

Novel series of bicyclic pyrrolo[1,2-c]pyrimidines 3a-g, 5, 6a, b, and 7a, b, tricyclic pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 8a-c, 9a-g, 13a-c, 17, 18a, b, 19, 20a,b and 21 and tetracyclic condensed pyrimidines 14, 22 and 23 were synthesized through different chemical reactions. Structures of all synthesized pyrimidine derivatives were supported by spectral and elemental analyses. Analgesic activity evaluation was carried out using acetic acid-induced writhing assay, and all compounds exerted comparable activity to indomethacin. The anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema in rats, the potency of the bicyclic derivatives 3a-f and 7b revealed comparable activity to indomethacin without gastric ulceration. The tricyclic derivatives 13a and 20a exerted good activity, however, they induced gastric ulcers while 13b and 13c showed moderate activity without ulceration. In case of tetracyclic derivatives, compound 14 exhibited the highest potency and safety profile.