Letters in Drug Design & Discovery - Volume 10, Issue 8, 2013

The promising cytotoxic and anti-angiogenic anticancer drug candidate Titanocene Y, which shows good in vitro and in vivo activity is now studied in connection with its mode of action and transportation by employing spectroscopic methods. The active transportation into the cancer cell via binding to serum albumin was investigated using a competitive displacement titration of the known serum albumin binder 8-anilino-1-naphthalene sulfonic acid in combination with fluorescence spectroscopy. The Gibbs free energy of the system was calculated to analyse the binding degree which was calculated at ΔG = -33±3 kJ/mol. After confirming the ability of Titanocene Y to bind to serum albumin a number of Titanocene dichloride derivatives were investigated. These derivatives varied in ligand substitution pattern and metal centre from vanadium and iron to silver, and displayed a binding degree range from -24 up to -34 kJ/mol. The difference in the determined value of Gibb’s free energy may help to establish the optimal metal and substitution pattern for binding and transportation into target cells. Furthermore, the possible interaction of Titanocene Y with DNA was investigated by UV-Vis and CD spectroscopy. UV-Vis spectroscopy monitored DNA interaction of Titanocene Y via thermal denaturation studies, while Circular Dichroism spectroscopy indicated an interaction between Titanocene Y and the DNA double helix at ambient temperatures. The binding to serum albumin indicates the transport of the metallocene to the cancer cell via protein binding where interaction with DNA may occur

The cytotoxic activity of two bioactive molecules obtained from Croton species, caracasine acid (monomer) and micansinoic acid (dimer) belonging to the group of the seco-ent-kaurenes was evaluated against the prostate cancer cell line PC3 and human dermis fibroblasts (control cells). In addition, the combination of the monomer and dimer was realized with the antitumoral drugs taxol and adriamycin. The PC3 and normal cells were growth-inhibited in a dosedependent manner after exposure to both natural products. These two seco-ent-kaurenes exhibited practically the similar cytotoxic activity against human tumor cells but not to normal cells. The monomer and the dimer in combination with adriamycin and taxol respectively showed a synergistic effect on tumor cells, resulting that the combination of adriamycin with the monomer or dimer was more effective than with the taxol. Moreover, the combination of monomer and dimers showed a strong antagonistic effect.

A novel series of Mannich bases of 1, 3-dihydroxyxanthone derivatives were designed and synthesized. The chemical structures of the compounds were characterized by IR, MS and NMR spectra. Their in vitro toxicities on six tumor cell lines including NCI-H460 (lung cancer), TCA-8113 (tongue squamous cell carcinomas), BEL-7402 (liver cancer), HepG2 (hepatocarcinoma), SGC-7901 (gastric carcinoma) and T24 (urinary bladder carcinoma) were studied through MTT assay. The results showed that most of the compounds displayed mild to good inhibitory activities on the cancer cell lines. Some preliminary structure-activity relationships were also discussed.

A new combination of reagent (ZnCl2/TBAB) system has been developed for the preparation of dihydropyrimidinones by using aldehyde, acetoacetic ester and urea or thiourea. These improved reaction condition allow the preparation of a wide variety of substituted dihydropyrimidinones in high yields and purity under mild reaction conditions. Some of the dihydropyrimidinones were showed moderate in vitro cytotoxic activity against U937, Colo205, A549 and THP-1 human cancer cell lines. Some of the compounds have been found promising anticancer activity when compared standard drug etoposide.

A Hybrid pharmacophore and structure-based drug design approach, aided by binding mode analysis, molecular dynamics simulations and per-residue energy contribution calculations, was used to design five novel structural scaffolds as potential bifunctional anti-HIV/TB inhibitors. Binding free energy calculations demonstrated that the proposed compounds exhibited better binding affinities towards HIV PR and BlaC enzymes when compared to prototype drugs, darunavir and meropenem, respectively. The lead design strategy presented in this work could serve as a useful tool for developing bifunctional inhibitors against wide range of biological targets.

In this present work, 5-chloro-3-(substituted-benzylidene)indolin-2-one and 1-benzyl-5-chloro-3-(substitutedbenzylidene) indolin-2-one derivatives were synthesized and evaluated for their inhibitory activity against Src Family Kinases (SFKs) such as Fyn, Lyn and Hck. 5-Chloro-3-(substituted)indolin-2-ones (3a - 6a) and 1-benzyl-5-chloro-3- (substituted-benzylidene)indolin-2-ones (3b - 6b) were prepared by condensation of 5-chloro oxindole and 1-benzyl-5- chloro oxindole with the equivalent amount of aldehydes in EtOH in the presence of piperidine. Among all compounds, only 4a, 5b and 6b were found slightly active against Fyn with 13 - 16% inhibitions at 0.1 and 0.01 mM concentrations. Compounds did not exhibit any inhibitory potency against Lyn and Hck. Docking study of compounds was performed to evaluate receptor-binding properties of compounds and the results showed that the most active compound 6b binds into the active site of Fyn, which has similar binding mode with potent inhibitor PP2.

The elevated level of dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is associated with the pathology of neurodegenerative diseases and has been implicated in some neurobiological alterations of Down syndrome, such as mental retardation. In the present article, a pharmacophore based 3D-QSAR model was developed for a series of leucettines possessing Dyrk1A inhibitory activity. The crucial molecular features observed in the developed pharmacophore model that account for binding affinity of ligands with the enzyme, include three H-bond acceptors (A), one positive ionic site (P) and one hydrophobic aromatic ring (R). Excellent statistical results of QSAR model such as good correlation coefficient (r > 0.9), higher F value (F > 20), excellent predictive power (Q2 > 0.6) and higher enrichment of known actives during virtual screening application strongly suggest that the developed model will be highly useful in designing new inhibitors and for predicting activity of new inhibitors.

In order to discover novel MEK inhibitors, a series of 3-(benzothiazol-2-yl) coumarin derivatives have been synthesized following our earlier study of 3-benzyl coumarin derivatives. The target compounds were obtained by condensation, cyanation, hydrolyzation and esterification starting from o-hydroxy benzaldehydes and benzothiazole-2- acetonitrile. The cyanation reaction could only occur when there were electron with drawing groups at C3 position of coumarin scaffold. All the synthesized compounds showed weak binding and inhibition potencies to phosphorylated MEK1 but obvious inhibitory effect to unphosphorylated MEK1, suggesting that compounds inhibition to MEK1 is mainly due to the inhibition of npMEK1 rather than pMEK1. The most potent compound 3 was with an inhibition rate of 60.7% at 1 μM in the RAF-MEK cascading assay. Molecular docking studies revealed that the pocket occupation and structure hydrophobicity may be important for activity. These results can contribute to further optimization on coumarin scaffold and led to the design of novel coumarin derivatives as more potent MEK1 inhibitors.

The synthesis of Etidronate (as the disodium salt) by the reaction of acetic acid with phosphorus trichloride/ phosphorus acid in methanesulfonic acid was studied and optimized. We showed that it is enough to use 3.2 equivalents of the phosphorus trichloride and there is no need to apply phosphorus acid. In the two-step variation of the synthesis, the acetyl chloride was formed by the reaction of acetic acid with phosphorus trichloride, thionyl chloride or triphosgene, then the intermediate was converted to etidronate by reaction with 2.2 equivalents of phosphorus trichloride. The work-up included in all cases hydrolysis and pH adjustment.

The solid-phase synthesis of di-N-acetyl-β-chitobiosyl N-glycoaminooxazoline 2 was studied. The synthesis was gone along using the N-benzyloxycarbonyl (Cbz) protected trichloroacetimidates 11 and 13 as donors, polystyrene as support, and o-nitrobenzyl ether tether as linker. The compound 2 was high-efficiently offered by three glycosylations, catalytic hydrogenolysis, acetylation, deacetylation, and photolysis, respectively.

Chloroquine has been widely used to treat malaria, however, it is currently largely ineffective due to widespread parasite resistance. In this work, five 6-mercaptopurine derivates were synthesized and their in vivo antimalarial activity was examined. Among the three derivates of 6-mercaptopurine containing 1,2,3-triazole, compound 16 stands out, which showed increased activity over the days analyzed, inhibiting the growth of parasites in a way similar or even superior to chloroquine. Also, among the derivates of 6-mercaptopurine containing steroid, the analog 18 exhibited suppression of parasitaemia close to that of chloroquine. None of compounds showed cytotoxicity against mammalian cells.

Twenty-two 4-aryl/alkyl-1-(diphenylacetyl)thiosemicarbazides were synthesized and their in vitro antibacterial potency was evaluated. 4-(4-Chlorophenyl)-1-diphenylacetylthiosemicarbazide showed comparable activity to control antibacterial ampicillin against Gram-positive species with MICs range 3.91-15.63 μg/mL. The compound was also tested for its cytotoxicity against L929 cell line using the MTT assay technique. The results of antibacterial activity and toxicity test indicated that it display antibacterial activity at non-cytotoxic concentrations. Finally, some structural and electronic parameters have been determined in hope to get insight into different biological activity of closely related isomers.

Several 4H-pyrano[3,2-h]quinolone (3, 5, 7, 8, 10, 11, 14, 15, 16 and 17) and 7H-pyrimido[4',5':- 6,5]pyrano[3,2-h]quinoline derivatives (9, 12, 13, 18) were prepared. These compounds were tested in vitro for their antimicrobial activity to show congruent results against the most tested microorganisms as compared with the standards Ampicillin, Streptomycin, Mycostatine and Clotrimazole. The structure activity relationship (SAR) studies of 3 and its analog compounds revealed higher potent antimicrobial activity against the most tested microorganisms. These data indicated that the activity of compounds was considerably attributed to the presence of the electrondonating groups in combination with the electron-withdrawing groups in 4H-pyrano[3,2-h]quinoline moiety. Incorporating a pyrimidine nucleus with pyranoquinoline moiety resulted in changing the potency for some compound. The structures of these compounds were established on the basis of spectral data.

A series of 16 novel 4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-(substituted-phenyl)pyrimidin-2-ol analogues was synthesized in satisfactory yields after toxicity prediction and drug score studies by Osiris software followed by anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation activities of 10 compounds by the known reported methods. 4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-(4-chlorophenyl)pyrimidin-2-ol (6g) was found to be a potent compound of the series showed good anti-inflammatory (81.91 ± 7.69 % inhibition) and analgesic activity (53.25 ± 2.91) with less ulcerogenic effects (0.66 ± 0.40).

A series of new 2,5-disubstituted-1,3,4-oxadiazole derivatives 8(a-o) was synthesized by the reaction of 1-(5- phenyl-1,3,4-oxadiazol-2-yl)piperazine with various sulfonyl chlorides. The synthesized compounds were characterized by elemental analyses,1H NMR 13C NMR and mass spectral studies. The newly synthesized compounds were screened for their anticonvulsant activity against maximal electroshock (MES) seizure method and compared with the standard drug phenytoin. The neurotoxic effects were determined by rotorod test. Compounds 8d, 8e and 8f were found to be most potent of this series. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). The efforts were also made to establish the structure activity relationships among synthesized compounds.