Letters in Drug Design & Discovery - Volume 13, Issue 8, 2016

Background: For studying the antioxidant activity a synthesized 1,3-bis(3-phenylpropyl-1)- 1,3-dihydro-2H-benzimidazol-2-imine hydrobromide (M1) has been chosen because of its most pronounced antiproliferative effect (preliminary studies) to human colorectal cancer cell line HT-29, breast cancer cells MDA-MB-231 and its nontoxicity to normal Lep 3, determined by means of MTS-test. It is believed that this suppressive activity is due to its antioxidant capacity. Other two new linear somatostatin analogs which contain hydrophobic aminoacids 3c (D-Phe-c(Cys-Phe-D-Trp-Lys-Tle-Cys)-Thr-NH2) and 3L (Pro-Phe-Val-Tyr-Leu-Ile-D-Trp-Lys-Tle-Thr-NH2) were tested for their toxicity to the same cells and all experiment substances were tested to activated macrophages. Methods: the ROS-scavenging ability was examined (by HORAC and ORAC) using the same cells and the obtained results confirmed a considerable suppressive capacity of the compounds. Results: The compounds 3c and 3L exerted the most pronounced inhibition of the tumor cell vitality (up to 77%) at higher concentrations and were not toxic to normal Lep-3 cells. After similar incubations with the substances activated human peritoneal macrophages displayed also emission of ROS determined by chemiluminiscence (CL). Compound M1 showed pronounced activity against activated peritoneal macrophages (PMA) mainly in the 100000x dilution in comparison to the HORAC and ORAC; 3L is most effective only in the 100x concentration. Conclusion: All tested compounds showed different suppressive activities depending on the cell line and on the substances amount applied by performing HORAC / ORAC and CL investigations.

A novel tamibarotene derivative was synthesized by coupling cytotoxic agent 5-Fluorouracil (5-FU) with tamibarotene via ester. This hybrid drug (compound 10) was evaluated for its antiproliferative activities against human leukemic U937, HL-60 and K562 cell lines in vitro. Results showed that compound 10 exhibited more potent anti-leukemic activity than the positive control tamibarotene. Furthermore, the preliminary stability test of compound 10 revealed that it could release tamibarotene and 5-FU significantly in vitro. These interesting results would be meaningful to develop more potent drugs for the treatment of human leukemia.

N,N’-bis[1-(substitutedphenyl)-3-(morpholine-4-yl)propylidene]hydrazine dihydrochlorides, N1-N11 were designed and synthesized as cytotoxic agents. These compounds were synthesized by the reaction of 2 moles of 1- (substitutedphenyl)-3-(morpholine-4-yl)-1-propanone hydrochlorides with 1 mole of hydrazine hydrate. The compounds reported here are new, except N1 and N4. The cytotoxicity of the compounds was tested against human hepatoma (Huh7) and breast cancer (T47D) cell lines. 5-Fluorouracil (5-FU) was used as a reference compound. It was found that N3, which has 4-methoxy substituent on phenyl ring, was the most cytotoxic compound towards both cell lines. Its cytotoxicity was 5.6 times higher than 5-FU. Representative compounds N2 at 144, 264 and 424 μM and N3 at 401 μM concentrations significantly inhibited mitochondrial respiration in a dose dependent manner in liver homogenates. This suggests that the inhibition of mitochondrial respiration may be one of the contributing mechanisms to the cytotoxicity of the compounds. N3 may serve as a candidate compound for further studies.

Melanin is a pigment distributed in the human body. The excess accumulation of melanin contents on skin surface induces mottling and freckles which are unfavorable for maintaining good health and beauty. On the other hand, gray hair is caused by the decreasing of melanin production. Hence, to maintain appropriate melanin level in human body is desired strongly. Melanin is biosynthesized in melanosome in melanocyte by catalysis of tyrosinase, tyrosinase related protein-1 (TRP-1), and TRP-2 from L-tyrosine as a starting material, and the mature melanosome is transported to the keratinocytes or hair matrix cells by several kinds of related proteins, such as melanoregulin (Mreg), EBP50-PDZ interactor of 64kDa (EPI64), Rab27A, Slac-2a, etc. The keratinocytes or hair matrix cells accumulate melanosomes, and the skin or hair pigmentation is appeared by the differentiation of the cells. In order to modulate the pigmentation of the tissue in human body, a number of melanogenesis modulating compounds have been isolated and identified from medicinal plants as tyrosinase activity inhibitors and/or modulators on melanogenic enzymes expressions. However, there are a few reports evaluating the effects of compounds on melanosome transportation which influence the control of pigmentation. Therefore, search for the novel compounds modulating melanosome transportation as well as modulating melanognesis is recently desired.

Time-dependent distribution of selegiline was monitored in various tissues of rabbits treated with a dose of 30 mg/kg intravenously. Selegiline content was determined by validated RPHPLC method following 5,15, 30, 60 and 120 minutes of treatment. The present study confirming earlier data showed that selegiline readily penetrates through the blood brain barrier, however, as a new result, high selegiline concentrations were measured in the lacrimal glands, lungs and testes as well as in the eyes of rabbits at each time point studied. When selegiline concentrations in the different eye segments were determined, a time-dependent decline of selegiline tissue levels was observed in the iris, the cornea and the intraocular lens, while the maximum level of selegiline in the retina found at 15 min and even at 60 min, was similar to that determined at 5 min following administration.

Quantitative structure-activity relationship (QSAR) and molecular modeling studies have been performed on a series of indole-based pyridone analogues as hepatitis C virus (HCV) NS5B polymerase inhibitors. A multiple linear regression (MLR) analysis has shown that the presence of hydrogen- bond donors in the molecule plays a negative role, but the substituents present on the indole ring sterically favor the activity of indole-based pyridine analogues. Using the MLR analysis model, some new analogues of indole-based pyridone with better potency have been predicted. Docking study has been performed on all the predicted compounds to study their binding modes with the receptor.

Acyclovir, a popular antiviral drug, is associated with the problems of poor water solubility, low bioavailability (15-30%), low permeability (across the gastro intestinal membrane) and short half-life (3 hours) leading to high dosage frequency which in turn may cause adverse effects. Therefore, with the objective of the improvement in solubility (and dissolution also) and gastro intestinal permeability (which in turn is expected to improve the bioavailability) of acyclovir, the acyclovir- β-cyclodextrin (β-CD) complexes were prepared and characterized. The inclusion complexes of acyclovir were prepared with β-CD (with or without the presence of hydrophilic excipients namely polyvinyl pyrollidone K-30 and nicotinamide) using the kneading method. The prepared complexes were characterized for various physicochemical properties, FTIR, DSC, XRPD, in vitro release and ex vivo permeation study. The effect of water soluble excipients (PVP K- 30 and nicotinamide) on the performance of acyclovir- β-CD inclusion complexes was also studied. FTIR, DSC and XRPD data confirmed the formation of inclusion complexes. The DSC explained and correlated the change in the endothermic peaks with the complexation and the solubility improvement. This study revealed that FK6 (Drug+β-CD+PVP K- 30 1.5%+ nicotinamide-14mM) and FK4 (Drug+β-CD+nicotinamide-14mM) ratio showed highest increase in solubility as compared to that of PVP K-30. The effect of two excipients (PVP K-30 and nicotinamide) was investigated on the solubility, dissolution and permeability of acyclovir. Nicotinamide was found to be more effective and promising water soluble excipients for the preparation of β-CD complexes as compared to PVP K-30.

The Objective of the present work was to enhance the solubility and dissolution profile of poorly water soluble BCS class II drug Tinidazole (TNZ). Microwave energy was utilized to prepare solvent free solid dispersions of TNZ and combination of TNZ with hydrophilic carriers as urea, gum acacia, β cyclodextrin (β CD), polyethylene glycol 6000 and polyvinyl pyrolidone Formulated solid dispersions were characterized by FTIR, solubility, microscopy, melting point and physical characterization by DSC and PXRD. Results revealed principal peak values in FTIR spectra of the drug remain unchanged in microwave-induced solid dispersions indicating no chemical interaction. Enhancement of solubility in microwave irradiated TNZ ranged from 7.52% to 55.02%, while for MSD TNZ: Urea it enhances from 9.70% to 86.82%. This may be due to conversion of crystalline to amorphous form, which was confirmed by differential scanning calorimetry and powder X-ray diffraction. Dissolution profile of the microwave irradiated TNZ enhanced by 22% and that of MSD TNZ: Urea by 25%. TNZ was interacted with β-CD and the docking enrgy was found to be -9.4558 kcal/mol. Binding energies of complex (TNZ: β-CD) has shown favourable electrostatic interaction. It was found that binding energies decrease after docking indicating stability of β-CD–TNZ complex.

The close structural similarity between cyclooxygenase (COX) isoforms and also the lack of potent selective COX-2 inhibitors with low side effects, stimulate the development of new highly selective COX-2 inhibitors. In this study, a group of imidazo[1,2-a]pyridines was designed, synthesized and investigated to identify potent and selective COX-2 inhibitors. In vitro COX inhibition assay showed that all derivatives were selective COX2 inhibitors with IC50 values in the highly potent 0.07-0.18 μM range and COX-2 selectivity indexes (SI) in 57-217 range. 2-(4- (methylsulfonyl)phenyl)-3-(morpholinomethyl)H-imidazo[1,2-a]pyri-dine (6f) which possessing p-methylsulfonyl phenyl at C-2 of imidazo[1,2-a]pyridine ring, exhibited the highest COX-2 inhibitory selectivity and potency. Molecular modeling and docking studies indicated that synthesized compounds have a binding similar to that of the known inhibitor SC- 558 and also methylsulfonyl group can be inserted into the secondary pocket of COX-2. The ability of synthesized compounds for inhibition of platelet aggregation was also determined. Our results demonstrated that 6f was the most potent platelet aggregation inhibitor as well.

A series of 2-((5-aryloxy-1-methyl-3-methyl-1H-pyrazol-4-yl)methylene) hydrazinecarboxamides (6a-6l) and 2-((5-aryloxy-1-methyl-3-phenyl-1H-pyrazol-4-yl)methylene) hydrazinecarboxamides (7a-7l) were designed and synthesized. The maximal electroshock shock (MES) and subcutaneous pentylenetetrazole (sc-PTZ) seizure models in mice were used to evaluate the antiepileptic effect of compounds synthesized. Further, the acute neurotoxicity profile was also studied via the rotarod test. The results of sc-PTZ test indicate that a majority of compounds possessed anticonvulsant activity with long duration of protection effects. Among of them, compound 6k was found to be the most promising one, with an ED50 value of 20.4 mg/kg (in sc-PTZ model) and a PI value of 10.8, possessing higher anti-PTZ activity and wider safety margin than valproate and ethosuximide.

With the help of computer-aided drug design approach, five dabigatran derivatives were designed and synthesized. The structures of these compounds were elucidated by 1H NMR, 13C NMR, HRMS analyses. All the compounds were evaluated for their thrombin inhibitory activitiy in vitro (IC50) and they showed significant thrombin inhibition with IC50 values from 2.74 to 20.31 nM. Especially, compound 7a, and 7b were potent thrombin inhibitor with IC50 values of 2.74 and 2.99 nM, respectively, which were comporable to dabigatran (1.20 nM) and much better than argatroban (9.88 nM). Moreover, molecular docking study was performed to determine the inhibitory mechanism of active compounds.

A series of thirteen (2E)-1-[4-({6-nitro-2-[(E)-2-phenylvinyl]quinolin-4-yl}amino)phenyl]- 3-[(substituted) phenyl]prop-2-en-1-ones (5a-5m) were synthesized by five-step synthesis starting from 4-nitroaniline via 2-methyl-6-nitroquinolin-4-ol (2), 4-chloro-2-methyl-6-nitroquinoline (3), 4- chloro-6-nitro-2-[(E)-2-phenylethenyl]quinoline (3), and 1-[4-({6-nitro-2-[(E)-2-phenylvinyl]quinolin- 4-yl}amino)phenyl]ethanone (5), respectively. Final chalcones 6a-6m were synthetized from 4 by condensation reaction with corresponding benzaldehydes (unsubstituted, 2-, 3- and 4-methyl-, 2-, 3- and 4-methoxy-, 2- and 4-fluoro-, 2-, 3- and 4-chloro-, and 4-trifluoromethylbenzaldehyde, respectively). Chalcones 6a-6m were characterized by IR, 1H NMR and MS spectroscopy deflate, is not presented. Antimicrobial and antifungal activity of the compound 6 was studied against the four bacterial types (Staphylococcus aureus MTCC 96, Streptococcus pyogenes MTCC 443, Escherichia coli MTCC 442, Pseudomonas aeruginosa MTCC 441) and three different types fungal strains (Aspergillus niger MTCC 282, Aspergillus clavatus MTCC1323, Candida albicans MTCC 227). From the above synthesized compounds the chalcones 6e, 6f, 6k, and 6m exhibited very good activity against studied gram-positive and gram-negative bacterial strains and compounds 6a, 6e, 6f, 6j 6k and 6m showed very good anti-fungal activity against fungi above.

ATP-dependent xenobiotic efflux transporter P-glycoprotein (P-gp) limits the cellular accumulation of many therapeutically important drug molecules. The most prominent of these are CNS active compounds and the potential chemotherapeutic agents. Co-administration of chemotherapeutic agents with modulators of P-glycoprotein has been advocated as a promising concept to circumvent drug resistance in tumor cells. Several pharmacoinformatics strategies to investigate ligand-P-glycoprotein interactions profiles revealed that these are promiscuous, multi-site and conformational dependent processes that take place in asymmetric 3D space within the binding cavity of P-gp. Therefore, avoiding stereoselectivity associated with ligand-protein interaction may compromise efficiency of the QSAR and other modeling strategies. Within this article, several SAR and QSAR strategies in combination with molecular docking studies on stereoisomeric inhibitors of P-gp will be highlighted to further explore the stereoselectivity of ligand-P-glycoprotein interaction.

A series of novel 3-[2-(4H-1,2,4-triazol-4-yl)ethyl]-1-alkyl-1H-indole derivatives (4a-s) were synthesized and evaluated for their anticonvulsant activity and neurotoxicity by using maximal electroshock (MES) and rotarod neurotoxicity (TOX) tests. Among the compounds studied, compound 3-[2-(4H-1,2,4-triazol-4-yl)ethyl]-1-nonyl-1H-indole (4p) was found by intraperitoneal (i.p.) administration in mice to be the most potent compound with a median effective dose (ED50) value of 10.2 mg/kg, possessed better anticonvulsant activity and higher safety than carbamazepine.

Chromone derivatives, which have activities on the central nervous system (CNS) may be of great importance for finding out drugs for treatment of CNS disorders. Discovery of natural products with affinity for serotonin or 5- hydroxytryptamine (5-HT) receptors is the limelight of current research. Hence, the current objective of the present work is to study the 5-HT2B antagonist activity of 2-(2-phenylethyl)chromone (PECs) derivatives (3-6), which were previously reported from Cucumis melo L. using in silico studies. RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6- isopropylpyrimidine) was used as a standard. Docking studies identified specific amino acid residues through which the tested PECs derivatives bound with 5-HT2B receptor. Where, 3 showed highest binding affinity among tested compounds. Flexible alignment showed that all PECs derivatives aligned fairly well compared with reference compound except for 6. The results were quite encouraging for all PECs derivatives.