Letters in Drug Design & Discovery - Volume 9, Issue 2, 2012

The antimycobacterial activity of new 18 7-chloroquinoline derivatives, obtained from 4,7-dichloroquinoline, was evaluated against 15 Mycobacterium spp among standardized and clinical isolates using the MTT susceptibility test to obtain minimum inhibitory concentration values (MIC, μg/mL). The results suggested that 7-chloroquinoline compounds are useful leads for new anti-TB drug development. The most active compounds exhibited moderate activity with 16 μg/mL MIC values for all tested microorganisms.

Twenty-eight acyl hydrazides (1-28) are subjected for nitric oxide scavenging activities and their structureactivity relationship (SAR) is established. Compounds 1-28 showed a varying degree of activity having IC50 values in the range of 9.1 ± 6.5 - 231.1 μM. It was found that twenty-five (25) out of twenty-eight (28) compounds, showed an excellent nitric oxide scavenging activity. It was observed that the activity mainly depends on the substitution on acyl hyrazide moiety. 3-Propylpyrozole-5-carbohydrazide (27) was found to be the most active in the series with an IC50 value of 9.1 μM. Thus, compound 27 may serve as a lead compound for further development as potent antioxidant agent.

There was a major interest in the last years in the design of anticancer agents containing the 1,5-diaryl-3-oxo- 1,4-pentadienyl system. The modification of this pharmacophore by the introduction of an additional Michael acceptor represents a strategy to obtain novel potential antiproliferative agents. In a continuing study of hybrid compounds containing the α-bromoacryloyl moiety as potential anticancer drugs, we synthesized two novel series of hybrids 3a-i and 4a-i, in which this moiety was linked to the 1,5-diaryl-1,4-pentadien-3-one system. Many of the conjugates prepared (3b, 3c and 3g) demonstrated pronounced antiproliferative activity against five cancer cell lines, being more active than the reference compound Melphalan. Compounds 3e and 4b were also examined for their effects on the cell cycle progression of K562 cells. The detection of a sub-G1 peak upon incubation with these compounds suggested that 3e and 4b also exert their growth inhibiting effects by induction of apoptosis.

With a view to the rational design of a series of selected 42 substituted 1,3-diaryl propenone derivatives, quantitative structure-activity relationship (QSAR) models have been developed for the prediction of antimalarial activities against chloroquine-resistant strain of Plasmodium falciparum (W2). The statistically significant 2D-QSAR model having r2 = 0.7518 and q2 = 0.6628 with pred_r2 = 0.7189 was developed by GA-PLS and best Group based QSAR (GQSAR) model having r2 = 0.7890 and q2 = 0.7043 with pred_r2 = 0.7297 was developed by SW-MLR method. The three-point pharmacophore hypothesis yielded a 3D-QSAR model with good PLS statistics results (r2 = 0.985, Q2 ext = 0.967, F = 312.7, rpret 2 = 0.969, SD = 0.059, RMSE = 0.083, Pearson-R = 0.996). The results of 2D-QSAR, GQSAR and atom-based 3D-QSAR studies give detailed structural insights as well as highlights important binding features of these substituted 1,3-diaryl propenone derivatives as antimalarial agents which can provide guidance for the rational design of novel potent P. falciparum growth inhibitors.

A series of novel quinolinylhydrazones (5a-f) was synthesized by the condensation reaction of 2,6-diarylsubstituted piperidin-4-ones (4a-f) with 7-chloro-4-hydrazinoquinoline (2). Novel quinolinylhydrazones containing Shiff bases 8a-f and 11a-f were obtained via the condensation of Shiff bases 7a-f and 10a-f with 7-chloro-4-hydrazinoquinoline. These synthesized hydrazones were screened for their in vitro antimalarial activities to chloroquine - sensitive (T96) and chloroquine - resistant (K1) strains of P.falciparum. Among the synthesized compounds, 11a exhibited strong antimalarial activity at IC50 of 103.4 ng/mL and 18.76 ng/mL to both strains of P.falciparum, respectively.

Chinese traditional medicine uses luteolin for treatment of hypertension, inflammatory diseases, and cancer. Luteolin inhibits NF-κB activity at low micromolar (μM) concentrations, and does not exhibit any cytotoxic effects up to 100 μM. In this paper, we predict and analyze the ability of luteolin to inhibit TNF-α and NF-κB pathways including TNFR1, TRADD, TRAF2, RIP1, and IKKβ. Homology models of TNF-α and NF-κB pathways, including TNFR1, TRADD, TRAF2, RIP1, and IKKβ, were constructed using the Swiss-Model protein-modeling server, and verified by PROCHECK, VERIFY3D and ERRAT software. Protein-ligand interactions were determined by executing docking the six TNF-α and NF-κB pathway models, including TNFR1, TRADD, TRAF2, RIP1, and IKKβ, with luteolin using AUTODOCK 4.0 software. We used AUTODOCK 4.0 and LIGPLOT software packages to provide analysis of binding sites. Results indicate that luteolin binds to TNFR1, TRADD, TRAF2, and RIP1 through covalent bonding. Thus, luteolin may inhibit the TNFR1, TRAF2, TRADD, and RIP1 from complexation. Luteolin may also block the ATP binding sites of IKKβ, which inhibits tyrosine and serine kinases by competing with ATP binding sites and reducing the ability of IKKγto recruit the IKK complex to RIP following stimulation of TNF-α, by blocking the IKKβ substrate binding site. Therefore, luteolin is an effective inhibitor of the NF-κB pathway including TNFR1, TRADD, TRAF2, RIP1, and IKKβ.

A series of SMMC7721 inhibitors with a dehydroabietyl skeleton were synthesized from dehydroabietic acid and dehydroabietylamine, respectively. Their preliminary biological tests show promising antitumor activities against SMMC7721 cells. The molecular structural features of compounds are presented by molecular descriptors (geometrical, topological, quantum mechanical, and electronic) calculated using the Codessa software. Statistical modeling is built by using Codessa software using its best multilinear regression method to reveal the quantitative relationship between the structure and the biological activity. The results from the QSAR analyzes show the antitumor activity against SMMC7721 cells of the studied compounds is strongly dependent on Max atomic orbital electronic population, Max resonance energy for a C-C bond, Min nucleoph. react. index for a C atom and Max atomic state energy for a C atom. Such results are of great benefit to synthetic efforts to discover better SMMC7721 inhibitors.

Present work describes the atom based 3D QSAR analysis using pharmacophore based alignment to explore the essential three dimensional structural feature requirements of study molecules for better antagonism of P2X7 receptor. The best pharmacophore model (HPRRR.13) was developed and used to align study molecules for 3D QSAR analysis. The best QSAR model (HPRRR.134) generated with PLS factor 4 showed good values of statistical parameters i.e. R2 training, SD, F-value, q2 test, and Pearson-rtest. Moreover, the contours of different properties generated using best model were able to explain the variation in the activity of dataset with respect to these properties. The best pharmacophore model was subjected to screen in-house database where it picks some molecules that are reported as COX-2 inhibitors in the literature. Therefore, generated pharmacophore based 3D QSAR model may successfully be used to design new potent congener representatives.

Seven novel 3-(1-(2-(2,7a-dihydrobenzo[d]thiazol-2-ylthio)acetyl)-5-substituted-phenyl-4,5-dihydro-1Hpyrazol- 3-yl)-2H-chromen-2-one derivatives were synthesized and characterized by 1H NMR and 13 C NMR. All of the compounds have been screened for their anticancer activity. The bioassay tests show that compound 4g exhibited potentially high activity against human gastric cancer cell SGC-7901 with IC50 value of 6.99±1.10 μg/mL. Docking simulation was performed to position compound 4g into the telomerase (3DU6) active site to determine the probable binding model.

For this study, a series of 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (1-12) were synthesized by condensation of 4-amino-5-substituted-3-mercapto-1,2,4-triazoles with various benzoic acids through a one-pot reaction. The anti-inflammatory and analgesic activities as well as gastrointestinal irritation liability of the obtained compounds were evaluated. Several of the synthesized compounds showed noticeable analgesic and anti-inflammatory activity. For the active compounds a very low ulcerogenic index and diminished oxidative damage in stomach were observed. Moreover, title compounds were screened for their antifungal and antibacterial activities. Antifungal activity of the compounds was found better than that of their antibacterial activity.

The purpose of this research was to study the effect of zeolite powder, with particles size range between 53 and 1180 μm, on the stability and release of vitamins A, D3 and E. Zeolite type, chemical and morphological features were studied using SEM and XRF. High performance liquid chromatography was used to investigate the extracted vitamins from zeolite powder. The powder emanating from natural Iranian zeolite was first plunged into each saturated solution of vitamins A, D3 and E. The powders were then taken in laboratory condition for 2 h, 1, 2, 3 and 4 weeks at room temperature. The amount of the extracted vitamin constantly decreased with time in the control sample (without zeolite powder), whereas it remained steady in the zeolite containing sample. The amount of stable vitamin in ambient environment after 4 weeks was higher than the control sample due to the zeolite with particles size range between 710 and 850 μm. For simulated gastrointestinal pH, the amount of release from the sample with zeolite was also more than the control sample. Based on the results obtained from HPLC experiments, zeolite powder enhanced the stability of the system in acidic pH and increased the amount of vitamins released in gastrointestinal condition.

A series of aryloxypropyl derivatives have been synthesized and evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypy assays in mice and the compounds displayed good efficacy coupled with an atypical profile. Investigation of the selected physicochemical parameters important for CNS activity suggested a good potential for CNS activity. All compounds showed excellent compliance with lipinski's rules for oral and CNS activity. Good physicochemical similarity was noted for the test compounds with respect to standard drugs and good brain permeation was suggested by their log BB values computed through an online software program.