Letters in Drug Design & Discovery - Volume 13, Issue 3, 2016

Based on the structure of the previously identified leads, new series of compounds containing 1,2,4-oxadiazole core was designed. A small, diverse library of 51 compounds including both 2-(acylamino)ethyl and 2-ureidoethyl side chains was synthesized using parallel chemistry and tested for antiproliferative activity against prostate cancer DU-145 cell line. Four hit compounds – all belonging to 2-ureidoethyl series – were identified and three compounds were confirmed as 10-20 μM inhibitors. The similarity in compounds’ periphery and the data obtained previously suggest a similar mode of action for these compounds which was postulated as tubulin inhibition and was confirmed by in silico docking. These data provide further evidence for the privileged character of 1,2,4-oxadiazoles in antiproliferative compound design.

A series of symmetrical Schiff base derivatives (L1-L7) were designed by a one-pot condensation reaction of various aldehyde/ketone compounds with hydrazine under mild conditions (room temperature, 3 days), using ether as solvent and acetic acid as catalyst. The target products were characterized and analysed by 1H and 13C NMR, FT-IR and liquid chromatography mass spectrometry (LC/MS). Our research focuses on the identification of synthetically chemotherapeutic substances able to inhibit, delay, or reverse the process of carcinogenesis in several stages. The target compounds presenting two regions for SAR evaluation were screened for their activity toward MDA-MB-241 breast cancer cell proliferation for the first time. Compound (1E, 2E)-1,2-bis(1-(3-nitrophenyl)ethylidene) hydrazine (L6) showed significant inhibitory activity (IC50 = 7.08 μg/mL).

An assembly of quinoline, triazole and oxime ether in a single molecular entity afforded a new template that has been used for the generation of a small library of molecules as potential cytotoxic agents. These molecules were synthesized successfully via a one pot multistep method using the copper(I)-catalyzed [3+2]-azide-alkyne cycloaddition (CuAAC) in water as the key step. All these compounds were synthesized in good to excellent yields and were screened for their inhibitory effects on the growth of four cancer cell lines in vitro. Some of these compounds showed encouraging cytotoxic effects against lung cancer cells and inhibition of PDE4 in vitro.

Brassinosteroids (BRs) are important plant hormones that play key roles in plant development and defense responses to environmental cues. To explore the inhibition mechanism of BR biosynthesis, we report the synthesis of novel triazole derivatives with dansyl moiety (YCZ-FD) as a fluorescent probe. Inhibition of YCZ-FDs against BR biosynthesis was investigated by an assay method using Arabidopsis grown in the darkness. We found that YCZ-FD1 displays highly fluorescent intensity. The maximum excitation and emission wavelengths were found at 326 and 542 nm, respectively. YCZ-FD1 inhibits the stem elongation of Arabidopsis seedlings with an IC50 value approximately 19.8 ± 1.1 μM. To verifythe primary sites of action of YCZ-FDs on the biosynthesis of GA and BRs, effects of coapplication of GA3 (1μM) and/or brassinolide (BL, 10 nM) on YCZ-FD1 treated Arabidopsis seedlings were investigated. We found that co-application of BL reversed the YCZ-FD1 induced dwarfism of Arabidopsis seedlings while GA did not.

Selective inhibition of 11β-hydroxysteroid dehydrogenase type (11β-HSD1) is considered to be a novel molecular target for treating obesity, metabolic syndrome and type 2 diabetes mellitus. Here we presented identification of 11β-HSD1 inhibitors, selected from combinatorial array of substituted 1,2,4-oxodiazoles, by means of molecular shape superposition screening with vROCS program and docking with HYBRID tool. 23 selected compounds showed strong hydrogen-bond interactions with critical residues such as Ser 170 and Tyr 183 as well as hydrophobic contacts with the rest of enzyme cavity. These substances can be promising for further development of novel potent and selective 11β-HSD1 inhibitors.

Cyclin-dependent kinase5 (Cdk5), involved in the processes of neuronal maturation and migration, is expressed in most tissues including proliferation cells. This research is aimed to use Cdk5 as a target for anticancer drug design. Virtual screening of Cdk5 by using Raccoon | AutoDock VS against the National Cancer Institute Diversity Set II has been performed. The selected compounds show binding energy between -10.43 to -8.53 kcal/mol and ligand efficiency values more than 0.40, which revealed 20 potential inhibitor candidates. Moreover, the binding energy of 10 compounds is related to their biological evaluation.These 10 inhibitors from NCI Diversity Set II serve as new Cdk5 inhibitors.

Enzyme urease plays an important role in several pathologies, such as urolithiasis, urinary catheter encrustation, hepatic encephalopathy, peptic ulcers, and gastric cancers. Its inhibition, therefore, has a major therapeutic significance. For this purpose, nine natural flavonoids 1-9 were evaluated for their urease inhibitory activity. Five of them (i.e. 1, 3, 7, 8, and 9) showed a urease inhibitory activity with IC50 values between 14.2 – 132.9 μM. Compounds 3, 8, and 9 showed a potent activity (IC50 =19.4 ± 1.39, 14.2 ± 0.30 and 17.7 ± 0.23 μM, respectively), in comparison to the standard urease inhibitor, acetohydroxamic acid (IC50 = 41.5 ± 1.50 μM). Furthermore, compounds 1, 7, and 9 exhibited a competitive mode of inhibition. Compounds 1, 3, 7, 8 and 9 were finally tested for cytotoxicity by using mouse fibroblast cell line (3T3 cell line) assay. Compounds 1, 3 and 7 were found non-cytotoxic, while compounds 8 and 9 showed some level of toxicity (IC50 = 18.75 ± 0.45 and 13.01 ± 0.70 μM, respectively). Present study identifies flavonoid 8 as a lead for further investigation towards designing novel urease inhibitors for the treatment of diseases associated with ureolytic bacteria.

PLD-301, a phosphate prodrug of clopidogrel thiolactone discovered by Prelude Pharmaceuticals with the aim to overcome clopidogrel resistance, was evaluated for its in vivo inhibitory effect on ADP-induced platelet aggregation in rats. The potency of PLD-301 was similar to that of prasugrel, but much higher than that of clopidogrel. The results of pharmacokinetic analysis showed that the oral bioavailability of clopidogrel thiolactone converted from PLD-301 was 4- to 5-fold higher than that of the one converted from clopidogrel, suggesting that in comparison with clopidogrel, lower doses of PLD-301 could be used clinically. In summary, PLD-301 presents a potent and orally bioavailable antiplatelet agent that might have some advantages over clopidogrel, such as overcoming clopidogrel resistance for CYP2C19-allele loss-of-function carriers, and lowering dose-related toxicity due to a much lower effective dose.

Aquaculture is currently the source of at least 50% of fish consumed worldwide. Microbes pose an immense threat to present day aquaculture industry. Vibrio anguillarum is one of the causative agents of large scale mortality of cultured marine fishes, especially Asian sea bass (Latescalcarifer). Antibiotic usage to control infection and diseases in aquaculture is the most prevalent choice due to their inexpensiveness and ease of administration. Aspartate β-semialdehyde dehydrogenase (ASADH) is the seminal enzyme involved in the biosynthesis of amino acids including lysine, methionine and threonine. ASADH is found only in microbes and plants, thus making it a hot target for antibiotic drug design and development. Caulerpin is an emerging drug with excellent antiviral, anti-bacterial, cytotoxic and anti-cancer activities. In this study, we used in silicoapproach to test the efficacy of caulerpin against V. anguillarum ASADH (VA). We modelled 3-D structure of VA and docked it with caulerpin. Docking results show that caulerpin binds VA with a high binding energy (-8.5kcal/mol). Molecular dynamics simulations support enzyme inhibitor interactions as evidenced by the RMSD diagrams. We also propose that caulerpin can be used as antibiotic against other microbes considering the homology of ASADH sequence shared among them.

Quantitative structure-activity relationships (QSAR) approach is one of the recommended approaches in finding the relationship between molecular structures of amino acids and the activity of peptide drugs. In this work, variable screening by stepwise multiple regression (SMR) technique, a multiple linear regression (MLR) model was built with a new descriptor of amino acids-SVGT. Predictive ability and robustness of the models have been analyzed strictly by both training set and test set, with squared cross-validation correlation coefficient (QLOO2) and squared correlation coefficient between predicted and observed activities (r2). Moreover, the rm 2 (overall) metrics is used to further improve the predictive ability of the QSAR models. The obtained models with the QLOO 2, r2 and rm2 (overall) were 0.943, 0.952 and 0.943 for antimicrobial peptides; 0.826, 0.978 and 0.713 for oxytocin; and 0.804, 0.956 and 0.786 for angiotensin- converting enzyme. Satisfactory results showed that SVGT can offer good account of relationships between activity and structure of peptide drugs.