Letters in Drug Design & Discovery - Volume 11, Issue 10, 2014

A series of novel salicylic acid-based 1,3,4-oxadiazoles derivatives coupled with chiral oxazolidinones were synthesized to screen for their in vitro antitumor activity against five human cancer cell lines. Some of these compounds showed good antitumor activities with IC50alues ranging from 31.19-57.21 µM. Among the tested compounds 11, 15, 19, 23, 24, and 34 showed broad-spectrum antitumor activity against all the cell lines. In particular, compound 19 revealed remarkable antitumor activity with IC50 = 31.19-41.87 µM. A431 was the most sensitive cell line against all the compounds studied, followed by HeLa, MCF-7, A549 and HepG2. Structures of newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and HRMS spectral data.

Cholinesterase plays a vital role in the decline of cholinergic transmission and thus can contribute to the development of Alzheimer’s disease (AD). Thus, compounds that can inhibit acetylcholinesterase (AChe) and butyrylcholinesterase (BuChe) are the potential drugs for the treatment of AD. A series of novel pyrrolopyrimidine derivatives was synthesized and evaluated for their inhibitory activity against cholinesterase by Ellman method. Among the ten newly synthesized compounds, 4-(4-((4-(difluoromethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoate was the most potent molecule identified with the IC50 values of 18 µM and 17 µM on AChe and BuChe respectively.

A new series of 3',4'-bis(3,4,5-trimethoxyphenyl)-4'H-spiro[indene-2,5'-isoxazol]-1(3H)-one derivatives was designed and synthesized. The cytotoxic effects of the synthesized compounds were evaluated on several different human cancer cells. Among them, compound 9e displayed the most potent in vitro antiproliferative activity with IC50 values of 0.07±0.01 µM on T47D cells. Another potent derivative 9h displayed an IC50 value of 0.12±0.07 µM against T47D cells, comparable to that of the positive controls (Colchicine Cisplatin Vincristine Vinblastine Doxorubicin Celecoxib). The structure-activity relationships were discussed and both anti-tubulin and COX-2 inhibitory effects were proposed for the developed compounds.

Background/Purposes: The objective of this study was to evaluate the inhibitory effects of acetylshikonin on bacteria in periodontal disease and the activities of trypsin-like protease and glycosidic enzyme of P. gingivalis in vitro. Methods: The inhibition activity of acetylshikonin against bacteria was identified by microbial sensitivity tests of broth dilution method on 96-microwell plate. Trypsin-like protease and glycosidic enzyme activities were measured by a fluorescence spectrophotometer. Results: The minimum inhibitory concentration of acetylshikonin on gram-negative were found to be 0.0625mg/ml, 0.125mg/ml, 0.125mg/ml, 0.25mg/ml, 0.25mg/ml and 0.5mg/ml, for S. intermedius, P. micros, P. acnes, L. acidophilus, A. viscosus and E. lentum respectively. Acetylshikonin showed extensive antibacterial activity against gram-negative bacteria, and it was more active against gram-positive bacteria. The acetylshikonin inhibited the activities of both trypsin-like protease and glycosidic enzyme by 45% and 95% with the final concentration of acetylshikonin from 0.0195 to 2.5 mg/ml. Conclusion: The inhibition activity of acetylshikonin on bacteria and its enzyme of trypsin-like protease and glycosidic may be essential to conquer periodontal ecological niche for treating periodontal disease.

Some 4-aryl-4H-chromenes 3a-h, 5a-g, 7a-g and 9a-g were obtained by reaction of 3-substituted phenol 1, 4, 6 and 8 with α-cyanocinnamonitrile derivatives 2. We explored the structure activity relationship (SAR) of 4-aryl-4Hchromenes with modification at the 4- and 7-positions. The antitumor activity of the synthesized compounds was investigated in comparison with the standard drugs Vinblastine and Doxorubicin using microculture tetrazolium (MTT) colorimetric assay. Some compounds were found to have good in vitro antitumor activity. The structure-activity relationship (SAR) study revealed that the antitumor activity of 4-aryl-4H-chromenes was significantly affected by the lipophilicity, the calculated Log P value and the balance between 7-hydrophilic or hydrophobic substituent and hydrophobic substituent on the benzene ring at 4-position. The structures of the newly prepared compounds were confirmed by elemental analysis and spectral data.

Trismus-pseudocamptodactyly (TPS) syndrome is a musculoskeletal disorder, caused by mutation in the perinatal MyH8 gene, leading to the incomplete opening of mouth and camptodactyly of fingers upon dorsiflexion of the wrist. MyH8 gene is relevant for muscle regulation, and it plays a significant role in muscle motor function, the hydrolysis of ATP, that is essential for the production of force for muscle movement. To understand the structural basis of TPS, we utilize a large number of software packages to estimate how the Arg674Gln mutation would affect the structure and stability of MyH8 gene product. The motor domain of MYH8 was modeled in order to know what are the interactions altered in the mutant protein. Further, we docked the ATP in the nucleotide binding region of both wild type and Arg674Gln mutant to understand the mechanism of action. Our strategy may be helpful for understanding the mechanism of regulation of muscle movements and the role of Arg674Gln mutation in TPS.

Pd/C-Cu mediated alternative and one-pot method has been developed for the synthesis of (Z)-3- methyleneisoindolin-1-ones as potential inhibitors of PDE4. The methodology involved coupling-cyclization of obromobenzamides with a range of terminal alkynes in a single pot to afford the target compounds in acceptable yields. Some of these compounds showed encouraging inhibition of PDE4 when tested in vitro that was supported by in silico docking studies.

In the present study, 5,5'-(1,4-phenylene)bis[3-(2-thienyl)-4,5-dihydro-1H-pyrazole-1-(4-arylthiazol-2-yl)] derivatives (3a-h) were obtained via the reaction of 5,5'-(1,4-phenylene)bis[3-(2-thienyl)-4,5-dihydro-1H-pyrazole-1- carbothioamide] (2) with phenacyl bromides. The synthesized compounds were investigated for their antimicrobial activity against various bacteria and Candida species. Among these derivatives, 5,5'-(1,4-phenylene)bis[3-(2-thienyl)-4,5- dihydro-1H-pyrazole-1-(4-(4-chlorophenyl)thiazol-2-yl)] (3b) and 5,5'-(1,4-phenylene)bis[3-(2-thienyl)-4,5-dihydro-1Hpyrazole- 1-(4-(4-methoxyphenyl)thiazol-2-yl)] (3d) showed notable antimicrobial activity.

Hydrazones are a group of compounds possessing diversified biological activity, anti-inflammatory and analgesic activities. There are also known xanthine derivatives possessing such activity. The aim of our study was to investigate if introduction of hydrazone moiety to 3,7-dimethylpurine-2,6-dion-1-yl acetic and butanoic acid derivatives would enhance the analgesic activity. The designed series of compounds were synthesized in a multi-step procedure. Their pharmacological activity was investigated in the writhing syndrome test. Based on the results the structure-activity relationship was discussed. From the synthesized group of twenty compounds, nineteen were tested in vivo. The analgesic activity of most compounds, except for compound 4, was higher than for acetylsalicylic acid in the writhing syndrome test. Our study showed that the introduction of hydrazone moiety generally enhances analgesic activity of xanthine derivatives, compared to derivatives with free carboxylic group, ester, benzylamide and hydrazide moieties. The presence of hydroxyl moiety or substituent with high electron density does not seem to be necessary for the activity of hydrazone derivatives.

Newer N-(6-substitutedbenzo[d]thiazol-2-yl)-2-((substitutedcarbamothioyl)hydrazinecarboxamides were synthesized having semicarbazone and thioamide as two hydrogen bonding domains attached between proximal and distal aryl rings with a view to explore prospective anticonvulsant candidates. For preliminary screening of synthesized compounds, two convulsant tests i.e. Maximal electroshock (MES) and subcutaneous Pentylenetetrazole (scPTZ) tests were performed. Rotarod test was performed to determine any possible neurotoxicity in the synthesized compounds. The result of anticonvulsant screening established the significant ability of compounds, 3i, 3j and 3m, to suppress the convulsions generated by electrical seizures and scPTZ induced seizures as compared to standard drugs phenytoin (PHY) and carbamazepine (CBZ). Molecular properties and Pharmacokinetic parameters of the titled compounds were also determined using Lipinski’s rule of five. The promising results encourage future investigation on the rational modification of this nucleus for development of better compounds.