Medicinal Chemistry

The crude alcoholic extract of the leaves of Aloe grandidentata Salm.-Deck showed significant antimicrobial activity (200 mg/ml), potent anti-inflammatory and chronic antihyperglycemic (100 mg/kg b.wt.) compared to standard positive drugs. Phytochemical studies of the potent extract revealed the isolation and characterization of seven compounds; two new compounds; 1,1',8,8'-tetrahydroxy -3 ' - acetyl -3-methyl -5,5 ' bianthracene -9, 9 ' ,10,10 ' -tetraone (2) and 1,6,8-trihydroxy–7–methoxy–3- methyl anthraquinone (3), five known compounds, β-sitosterol (1), emodin (4), chrysophanol (5), physicon (6) and β-sitosterol-3-O-β–D-glucoside ( 7 ). This is the first report of the isolation of emodin and β-sitosterol-3-O-β–D-glucoside from genus Aloe and physicon from family Liliaceae. All structures of the isolated compounds were determined using several spectroscopic techniques; UV, IR, MS, NMR ( 1 H NMR and 13 C NMR) and by comparison with literature data.

A series of five new 1-(substituted phenyl)-2-phenyl-4-(substituted benzylidine)-imidazole-5-one derivatives (or) 5(4 H )-imidazolones have been synthesised adopting 3 o A Zeolite as catalyst. These compounds were assayed for their antifungal activityon three different selected phytopathogens which disparately affects the Jowar crop (Sorghum Vulgare) of Poaceae family. Among the tested molecules, compound 18 exhibited potent inhibitory activity when compared to the Bavistine (Positive control).

Helicobacter pylori is a gram-negative bacterium that infects the luminal surface of the human gastric epithelium. Around one half of the world’s population is thought to be infected by this bacterium, which is able to develop diseases such as peptic ulcer or gastric cancer. Eradication of Helicobacter pylori is becoming increasingly difficult due to resistance to common antibiotics. In previous work we have shown that an essential protein, flavodoxin, constitutes a target for the development of novel, specific antibiotics against infection caused by this microorganism, and we have described compounds sharing the [(E)-2-R-vinyl]benzene scaffold that exhibit bactericidal properties against Helicobacter pylori cultures. Based on the affinity and activity of 24 such compounds we have now developed QSAR models for affinity and minimal inhibitory concentration that will guide the improvement of antibacterial compounds based in the [(E)-2-R-vinyl]benzene scaffold. The two models show high statistical correlation and predictive capacity. Discovering novel chemicals with specific antimicrobial properties against Helicobacter pylori , and presumably not affected by existing resistances, will be of great help for the treatment of the diseases associated with this bacteriu

G-Protein Coupled Receptors (GPCRs) have enormous physiological and biomedical importance, being the primary target of a large number of modern drugs. The availability of structural information of the binding site of the targeted GPCR plays a key role in rationalization, efficiency and cost-effectiveness of the drug discovery process. However, obtaining structural information on GPCRs using X-ray crystallography or NMR requires a large investment of time and is technically very challenging. This situation significantly limits the ability of these methods to have an impact in drug discovery for GPCR targets in the short term and hence there is an urgent need for other effective and cost-efficient alternatives. We present here a practical approach that integrates GPCR modelling with fragment based screening to provide structural insights on the H3 and H4 histamine receptor binding sites. This approach creates a cost-efficient new avenue for structure-based drug design (SBDD) against GPCR targets. We report here a success of using this protocol for the discovery of selective and dual H3 and H4 antagonists. Our fragment screen yielded 44 H3, 21 H4 selective and 20 dual fragment hits. These fragments were used to construct high- quality H3 and H4 models followed by binding site exploration and structure based virtual screening (VS). Overall, 172 compounds were purchased for testing based on the virtual screening results. Of the 74 compounds predicted to have dual activity, 33 had activity against one or other of the two receptors (44%), of which 17 had activity against both. Of the 19 compounds predicted to be H3 selective, 13 were active against H3 (68%) and 10 of these also had selectivity over H4. Of the 79 compounds predicted to be H4 selective, 36 were active against H4 (45%) and 2 of these also had selectivity over H3

The sequence, -D-Tyr-Pro-Trp-D-Phe- has been identified from Loloatin C as a promising pharmacophore model for developing new antimicrobial peptides. Most of the linear peptides designed based on this sequence exhibits strong antimicrobial activities against Gram-positive bacteria S. aureus , S. albus and Gram-negative bacteria E. coli strains with MIC values ranging from 15.6 to 62.5 μg/mL, although they are inactive against fungus C. albicans , multi-drug resistant bacterial MRSA and K. pneumoniae . The linear hexapeptide, H-Asp-D-Tyr-Pro-Trp-D-Phe-Asn-OH (L1) is confirmed the most active peptide among them. L1 possesses s table α-helix domain conformation which is similar to Loloatin C in membrane mimetic solution. All the tested peptides demonstrate low hemolytic toxicity to rabbit red blood cells with EC 50 values higher than 120 μg/mL and low cytotoxicity to mouse fibroblast cells. The successful simplication of Loloatin C to a short linear peptide simplifies the synthetic process and lowers costs of production. The discussion of structure-activity relationship is also included