Letters in Drug Design & Discovery - Volume 10, Issue 4, 2013

Inclusion complex of Atorvastatin (ATR) in β-cyclodextrin (β-CD) was prepared using co-evaporating technique. Characterization of the complex was carried out by the solubility method, X-ray diffractometry (XRD), differential scanning calorimetry (DSC), 1H, 13C and fluorine nuclear resonance spectrometry (NMR). It was testified that the inclusion complex was formed between βCD and ATR. The stability constant K1:1 and the 1:1 steochiometry of complexation were determined. 1H, 13C and fluorine NMR analysis confirmed the inclusion and to provide information on the behavior of ATR inside the cavity of βCD. The dissolution rate of ATR/β-CD complex prepared by the co-evaporating technique was investigated and compared with this of the pure drug. Analysis of the dissolution samples was made by reversed phase liquid chromatographic method. The overall results showed that the dissolution rate of ATR/β-CD was significantly higher compared to the free ATR.

A series of 3-styrylbenzimidamides were synthesized and biologically evaluated in a cell free FRET assay as potential BACE1 inhibitors. Some of the synthesized analogues were discovered to have moderate BACE1 inhibitory activities with IC50 values ranging from 9.3 to 295.8 μM. Molecular docking study proposed that the most potent compound (E)-2d bound to BACE1 differently in S3-S2' subpockets forming no polar interaction with the catalytic Asp dyad compared with the 3-styrylbenzimidamides. The results would contribute to the further optimizations on benzimidamide scaffold to achieve novel small molecular BACE1 inhibitors with improved potencies.

Inhibitors of Protein Tyrosine Phosphatase 1B (PTP 1B), a negative regulator of insulin signal transduction, have been explored as potential antidiabetic agents. In the present work a series of bromo-retrochalcones as PTP 1B inhibitors have been used for pharmacophore modeling, atom based 3D-QSAR and docking studies. A five-point pharmacophore with two hydrogen bond acceptors (A), two aromatic rings (R), and one hydrophobe (H) as pharmacophoric features was developed using PHASE. The pharmacophoric hypothesis was used to generate statistically significant 3DQSAR models. The best model showed good PLS statistics characterized by survival score (9.306), cross-validated r2 (Q2) (0.706), regression coefficient r2 (0.861), Pearson-R (0.853), and F value (76.4). Taken together, the Partial least square (PLS) generated 3D-QSAR pharmacophore and regression cubes along with structure based drug design provided a three dimensional topological view of the active site that can be used for the rational modification of bidentate PTP 1B inhibitors.

A series of novel 3-O-arylalkylbenzamide derivatives as FtsZ inhibitors was designed, synthesized and evaluated for their cell division inhibitory activity against B. subtilis and S. aureus, and in vitro antibacterial activity against various phenotypes of Gram-positive bacteria. This series showed significantly improved on-target activity and in vitro antibacterial activity compared with 3-MBA. Among them, 3-O-alkylbenzamids 4–8 and 3-O-bromoalkylbenzamides 9 and 10 showed significantly improved activity against three phenotypes of S. aureus ATCC25923, S. aureusATCC29213 (MRSA) and S. aureus PR. Preliminary structure-activity relationships indicated that the extension of 3-O-alkyl side chain resulted in a substantial improvement in the antibacterial activity, and the small group like methyl or ethyl group at the position 1–3 of the 3-O-alkyl side chain did not affect the antibacterial activity while the large group such as benzene or heterocycle at the position 4 or 5 of the 3-O-alkyl side chain could lead to poor antibacterial activity.

In search for the new antimicrobial agents owing to drug resistant bacteria and fungi, a series of rationally designed aza analogs of flavones has been designed and synthesized. The design of the analogs involved incorporation of quinolone nucleus within the flavone framework keeping in view the antimicrobial potential of both the classes. The series of compounds was evaluated for the antibacterial and antifungal activity against 3 Gram negative bacterial strains; E. coli (MTCC 82), S. typhi (MTCC 1251), P. aeruginosa (MTCC 2642), 2 gram positive bacterial strains B. subtilis (MTCC 2451), S. aureus (MTCC 96) and 2 pathogenic fungal strains, C. albicans (MTCC 3018), C. tropicalis (MTCC). The results of the antimicrobial evaluation clearly indicated the influence of the electronic factors linked with the aryl ring at the 2nd position with compounds bearing methoxy substitutents exhibiting significant antimicrobial profile as compared to the compounds bearing deactivating groups. The influence of placement of bicyclic, heteroaryl and bicyclic heteroaryl ring at the 2nd position of the analogs was also observed.

In the present investigation, it was of interest to synthesized some new derivatives of pyrimidine- 2,4,6(1H,3H,5H)-trione moiety incorporated with different biologically active pharmacophores such as thiazolidin-4- one, barbitone and 2-chloroquinoline-3-carbaldehyde. The structures of synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, and mass spectral data. Antimicrobial screening of title compounds were examined against Grampositive bacteria (Staphylococcus aureus and Streptococcus pyogenes), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and three fungal species (Candida albicans, Aspergillus niger, and Aspergillus clavatus) by serial broth dilution method. Compounds 6b, 6e, 6f and 6h were associated with considerably higher antibacterial and antifungal activities.

A series of 1,2,3-triazolyl quinolines possessing substituents like –CH2OAr (Ar = aryl) moiety on the triazolyl ring were synthesized via a multi-step sequence consisting of copper-catalyzed azide-alkyne cycloaddition (CuAAC) of 3- (azidomethyl)-quinoline derivative with terminal alkynes as a key step. This step was found to be remarkably faster in pure water and completed within 10-45 min. The robustness of this step was demonstrated by synthesizing a large number of compounds some of which showed promising antibacterial activities when tested in vitro. The crystal structure analysis of a representative compound along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.

A series of N-(2,4,5-trichlorophenyl)-2-Oxo- and 2-Hydroxycycloalkyl- sulfonamides (series II and III) were designed and synthesized based on the leading compound chesulfamide (code name: CAUWL-2004-L-13). Their structures were confirmed by 1H NMR, IR and elemental analysis. Compounds II and III showed excellent activities against the Botrytis cinerea both in vitro and in vivo. Mycelia growth and conidial germination assays exhibited that EC50 of compound IId were 0.64 μg mL-1 and 0.34 μg mL-1 respectively. For in vivo control of B. cinerea in cucumber seedlings, compounds IIb and IId showed better control effect than the commercial fungicides procymidone and pyrimethanil. In addition, these new compounds had broader fungicidal spectra than chlorothalonil. The fungicidal activity was affected obviously by the size of cycloalkane. All the compounds with six-, seven-, and eight-membered ring showed high fungicidal activities.

A series of new of 2-furano-4(3H)-quinazolinone derivatives 5 (a-t) were synthesized. The compounds were characterized by their IR, 1H NMR, 13C NMR, and Mass spectral data. The antimicrobial activity of newly anthranilic acid-based compounds against various bacteria; S. aureus, Salmonella enterica, Vibrio cholerae, Bacillus subtilis, Proteus mirabili, Escherichia coli V517, Mycobacterium smegmatics, Pseudomonas aeruginosa and fungi; C. albicans, were evaluated with ampicillin and amphotericin B as standards. All compounds were also evaluated for antibacterial activity against R. solanacearum along with Kocide 3000 as a commercialized reference. Compounds 5d, 5g, 5j, 5l, 5q, 5r, 5s, and 5t exhibited good potential as antimicrobial.

A series of diazepinomicin derivatives were synthesized and evaluated in vitro for their growth inhibitory activity against the human carcinoma cell lines. The results indicated the anticancer selectivity of this kind of compounds. Based on the results, preliminary structure-activity relationships were discussed.