Letters in Drug Design & Discovery - Volume 10, Issue 9, 2013

We have identified SRT2104 (4) as the first direct synthetic SIRT1 activator clinical candidate. The compound was derived from the optimization of a previously described imidazo[1,2-b]thiazole scaffold. SRT2104 was selected as a development candidate based on a combination of biochemical activity and pharmacokinetic profile. The in vivo characteristics of SRT2104 were superior to those of analogues with similar activation profiles. The overall preclinical profile suggests that the compound has potential to provide therapeutic benefit in a clinical setting.

Synthesis, characterization and investigation of antibacterial and antifungal activities of thirteen novel 6- hydroxybenzofuran-3(2H)-one based 2,4-disubstituted 1,3-thiazoles are presented. Their structures were determined using NMR, FAB MS and HRMS analyses. The results of microbiological screening reveal that three derivatives containing fluorine, bromine and hydrogen substituents at the phenyl ring are the most active antimicrobial compounds. Molecular docking studies of all compounds on the active sites of microbial enzymes indicated a possible target Nmyristoyltransferase (NMT).

Carbonic anhydrase (CA) IX is considered as a potential target for cancer therapy. In order to identify new scaffolds compounds and use them for designing novel CA IX inhibitors, herein 3D pharmacophore hypotheses had been established. Alignment and Scoring Engine (PHASE) software has been used to develop ligand-based pharmacophore model using a large set of 36 different aromatic/ heterocyclic sulfamates carbonic anhydrase inhibitors, such as CA IX chosen for the present study. In this study pharmacophore model was developed by downloading a large set of 36 ligands with Ki (nM) value from binding database. Ki ranged from >24 were considered as inactive and <24 nM were considered as active and found ligand 3ba as a templet molecule for the dataset chosen by PHASE. PHASE module of Schrodinger revealed the two hydrogen-bond acceptors, two hydrogen-bond donors, and one hydrophobic aromatic ring (AADDR.47) as crucial molecular features that predict binding-affinity of ligands to the hCA IX isoenzyme inhibition. The validity of each model predicted from the calculated correlation coefficient (q2) of 0.7049 and predicted squared correlation coefficient Q2 (r2pred) of 0.6280 for the test set confirms the good predictability of the QSAR model. The variant with a site score 0.89, vector score 0.952, volume score 0.654, and survival score of 3.497 was considered to be the best pharmacophore hypothesis. The information rendered by pharmacophore and 3D-QSAR modeling can provide guidelines for the development of improved hCA IX inhibitors as leads for various types of metastatic cancers including those of cervical, renal, breast and head and neck origin.

Hyperlipidemia is a common cardiovascular disease characterized by elevated lipid level in association with disordered lipoproteins metabolism. Atorvastatin, an HMG-CoA reductase inhibitor, has been developed as an antihyperlipidaemic agent and proved to exhibit antioxidant activity against lipid peroxidation. The two hydroxyl metabolites of atorvastatin, Ortho-hydroxy-atorvastatin and para-hydroxy-atorvastatin, are equipotent to their parent compound. Anethol trithione is a kind of liver protecting agent used to treat the hepatobiliary disease-related symptoms. Desmethyl anethol trithione, the degradation product of anethol trithione, keeps the related activity of anethol trithione and it is suitable for developing novel prodrugs. In this letter, a series of atorvastatin derivatives was designed as lipid regulators based on the structures of para-hydroxy-atorvastatin and desmethyl anethol trithione. Preliminary biological evaluation suggested compound 11a presented promising antihyperlipidemic, antioxidant activity and plasma stability.

Three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed for a series of ribonuclease H inhibitors using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and docking studies. A large set of 33 different aromatic/ heterocyclic N-hydroxy 1,8- naphthyridine 2-one analogs as Ribonuclease H inhibitors wher chosen for the present study. The naphthyridine ring of the n-hydroxy 1,8-naphthyridine 2-one gives the class of compounds which has the ability to chelate metal cations Mn2+ present in RNase H active. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q2 values 0.663 and 0.512 and r2 values 0.997 and 0.999 for CoMFA and CoMSIA respectively and the predictive ability of the model was also evaluated. The predicted r2 values were 0.660 and 0.650 for CoMFA and CoMSIA, respectively. Docking studies were employed to bind the inhibitors into the active site to determine the probable binding conformation. N-hydroxy 1,8-naphthyridine 2-one binds an RNA:DNA substrate, the RT/RNA:DNA structure (PDB code: 1HYS) was superimposed on our RT/N-Hydroxy 1,8-Naphthyridine 2-one (3QLH) structure (residues Val442 to Asp443, Glu478, and Asp549). Present study indicates that the CoMFA and CoMSIA models along with molecular docking could be reliable to establish a suitable molecular model which may be used in the design of novel ribonuclease H inhibitors as leads.

S1P1 is an important target from GPCR family, whose crystal structure was released recently. Here, for the first time, we perform the 3D-QSAR analyses on a series of pyrazole oxadiazole derivatives, which are potent S1P1 agonists, by CoMFA and CoMSIA. We use two basic common cores, oxadiazole and pyrazole-oxadiazole, to align all compounds to establish the models of COMFA and COMSIA. The best CoMFA model by applying region focusing achieved a q2 of 0.736 and an r2 of 0.968. The actual predictive capabilities of the best CoMFA and CoMSIA models were then confirmed by the satisfactory predictions for the test set: rpred2=0.762 for the best CoMFA model. Moreover, the contour maps derived from the best CoMFA and CoMSIA models are consistent with the biological activities of the studied compounds. Our results provide structural details about the interaction between S1P1 and small ligands. Our study is useful in guiding future design of more promising inhibitors of S1P1.

Cyclodextrins are capable to configure as a host-guest complexes in the company of hydrophobic molecules due to their emblematic nature imparted by their structural arrangement. The aim of present study is based on the application of in-silico tool for the selection of NSAID to develop novel drug delivery systems using β-Cyclodextrin. An understanding of the structural and binding properties of cyclodextrin with NSAIDs reveals the suitability of the combination for drug delivery purpose. Among various NSAIDs, Zomepirac containing –OH and -CO group demonstrated maximum moldock score accompanied by highest re-ranks score. Naproxen showed lowest score with no H-bond interactions with the cyclodextrin. The binding information obtained from the present studies can be mapped which will be helpful in the selection of polymers for the formulation of appropriate NSAID. The results of the present study may provide a new approach to select the polymers for the formulation of different therapeutic agents to achieve better pharmacological activity with minimal consequences of toxicity.

Metal complexes of 8-aminoquinoline (8AQ) derivatives were reported. This study presents a series of synthesized transition metal complexes of mixed ligands 8AQ-5-iodouracils (1-3) and 8AQ-5-nitrouracil (4-6) which have been investigated for their antioxidative and cytotoxic activities, as well as, powder X-ray diffraction patterns. Ni complex of 8AQ-5-nitrouracil (6) exerted significant cytotoxicity against MOLT-3 cell and superoxide scavenging activity. The results demonstrate an application of 8AQ molecule as a potential ligand for new bioactive compounds.

The 2-amino-6-trifluoromethyl-3H-pyrimidin-4-one 1 was propargylated to give two regioisomers 2, 3 in definite proportions. Both regioisomers 2 and 3 were independently reacted with alkyl, aryl or cycloalkyl substituted azides under Sharpless conditions and were obtained exclusively 1,4–disubstituted triazole tagged trifluoromethyl substituted pyrimidine derivatives 4 and 5 respectively. All the final products were evaluated for cytotoxic activity against four cancer cell lines and promising compounds were identified.

Three platinum (II) complexes (6-8) with phthalate as the leaving group were synthesized and characterized by FTIR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis. In-vitro cytotoxicity of all three complexes was evaluated using COLO 205 (human colon cancer cell line) against the parent drug “oxaliplatin”. The compound 4-amino-(transcyclohexane- 1,2-diamine) platinum(II) (8) showed potent cytotoxicity with IC50 = 0.12 μM as compared to oxaliplatin (IC50 = 0.19 μM) and its aqueous solubility was found to be 16 mg/mL which is higher than oxaliplatin (8 mg/mL). The acute toxicity showed that the platinum complex (8) was less toxic than oxaliplatin. Molecular oxaliplatin-DNA complex structure indicates that the diaminocyclohexane (DACH) and Pt (II) showed interactions with N7 and O6 of GG base pairs of DNA helix. In this present study, it is interesting to note that all three platinum based anticancer agents with phthalate as the leaving group exhibited great cytotoxicity, less toxicity, good lipophilicity as well as better aqueous solubility.

A series of novel β-carboline derivatives was synthesized and evaluated for their cytotoxic activities in vitro against two human tumor cell lines. Most of the compounds showed moderate to potent cytotoxic activities against the tested cell lines, in which compound 12l exhibited the most potent antiproliferative activities against KB cell line (IC50 = 4.58 μM). Preliminary mechanism research on compound 12l indicated that it could inhibit DNA intercalation and tubulin polymerization.

A set of new polyoxo 2-benzyl-2,3-dihydrobenzofurans and their related compounds, including 2- benzylbenzofuran-3(2H)-ones and 2-benzylbenzofurans, were designed and synthesized. Their antiproliferative activities were evaluated against human gastric cancer (SGC-7901), human fibrosarcoma (HT-1080) and human oral epidermoid carcinoma (KB) cell lines in vitro. Preliminary results showed that some polyoxo 2-benzyl-2,3-dihydrobenzofurans and their related compounds had significant activity comparable with that of cisplatin.

Previous studies demonstrated that hydantoin ibuprofen conjugates had effective anti-inflammatory and antitussive activities. In this study, we evaluated their analgesic and gastric ulcerogenic activities. Our results showed that these compounds retained analgesic activity from ibuprofen, more important, could suppress gastric ulceration. Furthermore, by analyzing the metabolites of the compounds in rat plasma using LC-MS/MS, we found that the compounds were hydrolyzed to hydantoin and ibuprofen, and then followed by ibuprofen conjugation to glucuronic acid.

A series of dihydropyridine analogous was synthesized and evaluated for anticonvulsant activity using PTZ animal model. The main strategies are introducing a non-classical dihydropyridine like structure as anti-seizure agent. Some compounds showed significant anticonvulsant activity in comparison with the control group.

A novel series of substituted thieno[3,2-d]pyrimidin-4(3H)ones 7-22 has been synthesized and evaluated for in vivo antihyperlipidemic activity using Triton WR 1339. Out of the 16 compounds synthesized and tested, 8 compounds have shown significant effect on total lipid profile. These compounds are several times more potent than gemfibrozil, the standard drug used for comparison. The superior activity of compounds 16 and 19 may be because of their esterase mediated metabolism into active metabolites. These compounds may serve to be ideal leads to provide newer antihyperlipidemic agents.