New 1,2,3-Triazole/1,2,4-triazole Hybrids as Aromatase Inhibitors: Design, Synthesis, and Apoptotic Antiproliferative Activity.

A novel series of 1,2,3-triazole/1,2,4-triazole hybrids 5a, 5b, and 6a-i was designed and synthesized as antiproliferative agents targeting aromatase enzymes. The antiproliferative activity of the new hybrids against four cancer cells was studied using Erlotinib as a control. Compounds 6a and 6b demonstrated the highest antiproliferative activity among these hybrids, with GI50 values of 40 nM and 35 nM, respectively. Compound 6b was the most potent derivative, with a GI50 of 35 nM, comparable to Erlotinib's GI50 of 33 nM. Compound 6b inhibited all cancer cell lines with comparable efficacy to Erlotinib. Compounds 5a, 5b, and 6a-i were tested for inhibitory action against aromatase as a potential target for their antiproliferative activity. Results revealed that compounds 6a and 6b were the most potent aromatase inhibitors, with IC50 values of 0.12 ± 0.01 µM and 0.09 ± 0.01 µM, respectively, being more potent than the reference Ketoconazole (IC50 = 2.6 ± 0.20 µM) but less potent than Letrozole (IC50 = 0.002 ± 0.0002). These findings indicated that compounds 6a and 6b had significant aromatase inhibitory action and are potential antiproliferative candidates. The findings were further linked to molecular docking investigations, which gave models of strong interactions with the aromatase domain for inhibitors with high binding scores.

Design, synthesis, and modelling study of new 1,2,3-triazole/chalcone hybrids with antiproliferative action as epidermal growth factor receptor inhibitors.

A novel series of 1,2,3-triazole/chalcone hybrids 6a-n was designed and synthesized using a molecular hybridization approach to develop a new cytotoxic agent capable of targeting epidermal growth factor receptor (EGFR) and/or BRAF. The antiproliferative effect of the novel hybrids was investigated against four cancer cells using doxorubicin as a reference. Hybrids 6a, 6d, 6f-h, and 6n have the highest antiproliferative activity (IC50 values 0.95-1.80 µM) compared to doxorubicin (IC50 1.14 µM). The most potent antiproliferative derivative, compound 6d, was also the most potent EGFR inhibitor with an IC50 of 0.09 ± 0.05 µM, which is comparable to the reference Erlotinib (IC50  = 0.05 ± 0.03 µM). 6d has modest BRAF inhibitory action with an IC50 of 0.90 ± 0.10 µM. The findings were also related to molecular docking studies, which provided models of strong interactions with the EGFR-TK domain for the inhibitors. In cell cycle analysis, hybrid 6d caused a cell cycle arrest at the G1 transition phase.

Synthesis, antimicrobial activity and molecular modeling study of 3-(5-amino-(2H)-1,2,4-triazol-3-yl]-naphthyridinones as potential DNA-gyrase inhibitors.

Four series of triazolylnaphthyridinone derivatives were synthesized as structural surrogates of nalidixic acid. The targeted derivatives involve: 3-(5-acylamino-2H-1,2,4-triazol-3-yl)-naphtyridin-4-ones 6(a-e); 3-(5-benzylidineamino-2H-1,2,4-triazol-3-yl)-naphthyridin-4-ones 8(a-g) and their 6-bromonaphthyridin-4-one analogs 7(a-e); 9(a-g). The synthesized compounds were evaluated In vitro for their antimicrobial activity against selected resistant strains of G+ve, G-ve, and Mycobacterium phlei. The results revealed remarkable selectivity, of the tested compounds, against Bacillus subtilis and Aggregatibacter actinomycetemcomitans, which are resistant to nalidixic acid. The growth inhibition zones were ranging from 20 to 40 mm at 10 mg/ml and the respective MIC-values ∼3.68-6.3 µM. The results illustrate that the 6-bromo derivatives 7(a-e) and 9(a-g) were more potent than the non-brominated counterparts 6(a-e) and 8(a-e) respectively. Inhibition of E. coli DNA-gyrase supercoiling activity is also evaluated. The 5-(4-methoxybanzamido)-triazolyl-6-bromonaphthyridinone (7e) exhibits IC50 = 1.94 µg/ml, which is comparable to that of nalidixic acid (IC50: 1.74 µg/ml). In addition, the most prominent IC50-values are displayed by: (7a;IC50: 2.77 µg/ml); (8g; IC50: 3.78 µg/ml); and (9d;IC50: 3.21 µg/ml). Molecular docking to the active site of DNA-gyrase cleavage complex of Acinetobacter baumannii (PDB code: 2xkk) co-crystallized with moxifloxacin revealed similar binding modes in addition to new interactions. Assessment of drug-likeness characteristics illustrate that the synthesized compounds showed agreement to Lipinski's and Veper's parameters. The study could offer an exceptional framework that may lead to the discovery of new potent antimicrobial agents.

Design, Synthesis, and Cytotoxicity Evaluation of Novel Griseofulvin Analogues with Improved Water Solubility.

Griseofulvin 1 is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Study of SAR of some griseofulvin analogues has led to the identification of 2'-benzyloxy griseofulvin 3, a more potent analogue which retards tumor growth through inhibition of centrosomal clustering. However, similar to griseofulvin 1, compound 3 exhibited poor aqueous solubility. In order to improve the poor water solubility, six new griseofulvin analogues 5-10 were synthesized and tested for their antiproliferative activity and water solubility. The semicarbazone 9 and aminoguanidine 10 analogues were the most potent against HCT116 and MCF-7 cell lines. In combination studies, compound 9 was found to exert synergistic effects with tamoxifen and 5-fluorouracil against MCF-7 and HCT116 cells proliferation, respectively. The flow cytometric analysis of effect of 9 on cell cycle progression revealed G2/M arrest in HCT116. In addition, compound 9 induced apoptosis in MCF-7 cells. Finally, all synthesized analogues revealed higher water solubility than griseofulvin 1 and benzyloxy analogue 3 in pH 1.2 and 6.8 buffer solutions.

Sensitive determination of trimetazidine in spiked human plasma by HPLC with fluorescence detection after pre-column derivatization with 9-fluorenylmethyl chloroformate.

A high-performance liquid chromatographic method for the determination of trimetazidine dihydrochloride (TMZ) in spiked human plasma is described. The method is based on the pre-column derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl) using the fluorimetric detection technique. Fluoxetine HCl (FLX) was used as internal standard. Both, TMZ and FLX were completely derivatized after heating at 50 degrees C for 20 min in borate buffer pH 8.0. Samples were analyzed by high performance liquid chromatography (HPLC) using Zorbax-TMS column (250 mm x 4.6 mm, i.d., 5 microm) and mobile phase consist of acetonitrile, methanol and 20 mM sodium acetate pH 4.7 (44:6:50; v/v/v). Fluorescence detector (FLD) was adjusted at excitation and emission wavelengths; 265 and 311 nm, respectively. The linearity of the method was in the range of 4.5-200 ng/ml. Limits of detection (LOD) and quantification (LOQ) were 1.5 and 4.5 ng/ml, respectively. Trimetazidine recovery was 96.5+/-1.3% (n=6; RSD=2.1%).

Brain delivery of HIV protease inhibitors.

To overcome the problems of peptidomimetic drug delivery to the specific organs, the use of dihydropyridine <--> pyridinium chemical delivery systems to deliver peptides to the brain is considered in this work. An HIV protease inhibitor lead compound; KNI 279 was selected for the study. The N-alkylated dihydroisoquinoline derivatives of KNI-279 were synthesized and tested for their ability to be oxidized by brain homogenate and showed good results with reasonable half-life times specially for the N-alkoxycarbonyl-methyl derivative 8. The in-vivo distribution of compound 8 proved the brain delivery and locked in property of HIV PR inhibitors in the brain. All the prepared compounds (both quaternary and dihydro derivatives) showed between 51 and 86 % HIV PR inhibitory activity compared to the parent compound.