Small molecule inhibitors of West Nile virus

West Nile virus is a human pathogen which is rapidly expanding worldwide. It is a member of the Flavivirus genus and it is transmitted by mosquitos between its avian hosts and occasionally in vertebrate hosts. In humans, the infection is often asymptomatic, but the most severe cases result in encephalitis or meningitis. Around 10% of cases of neuroinvasive disease are fatal. To date there is no effective human vaccine or effective antiviral therapy available to treat WNV infections For this reason, research in this field is rapidly growing. In this article we will review the latest efforts in the design and development of novel WNV inhibitors from a medicinal chemistry point of view, highlighting challenges and opportunities for the researchers working in this field

Computer-aided identification of novel anticancer compounds with a possible dual HER1/HER2 inhibition mechanism

HER1 and HER2 are frequently overexpressed in human tumors where they drive cellular proliferation. For this reason they are considered important targets in anticancer therapy with dual HER1/HER2 inhibitors being recently approved and marketed. In this paper we report the identification of a series of compounds with anticancer activity by a combined virtual screening approach on the kinase domains of HER1 and HER2. 6 hit compounds that present a sub- or low-micromolar activity in two cell-based assays, were initially identified and a subsequent design cycle led to the synthesis of a compound with nanomolar activity in the cell-based assays

SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL COUMARIN DERIVATIVES AS POTENTIAL ANTIMICROBIAL AGENTS

Objective: Synthesize new series of 7-hydroxy-4-methylcoumarin and 7-alkoxy-4-methylcoumarin derivatives featuring thiosemicarbazone or thiazolidin-4-one moieties and to evaluate their antimicrobial activity against two strains of Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), two Gram-negative bacteria (Escherichia Coli and Pseudomonas aeruginosa), and Candida albicans.Methods: Preparation of the new coumarin derivatives was done by adopting Pechmann condensation and attaching different isothiocyanates to give coumarin-thiosemicarbazone hybrids. Thiosemicarbazones were cyclized into thiazolidine-4-ones using chloroacetic acid or diethyl bromo malonate.Results: Compounds VIb, Xb, XIVb, and XVc gave the highest inhibition zones (>20 mm) against Staphylococcus aureus. Their MIC (minimum inhibitory concentration) values ranging from 0.19-0.36 µg/ml were better than the reference drug tobramycin with MIC= 2µg/ml.Conclusion: The newly synthesized compounds with the 7-hydroxyl group showed better antimicrobial activity than those with the 7-alkoxy groups.Keywords: Coumarin, Thiosemicarbazones, Thiazolidin-4-ones, Antimicrobial activit

Small Molecule Inhibitors of West Nile Virus

West Nile virus is a human pathogen which is rapidly expanding worldwide. It is a member of the Flavivirus genus and it is transmitted by mosquitos between its avian hosts and occasionally in vertebrate hosts. In humans, the infection is often asymptomatic, but the most severe cases result in encephalitis or meningitis. Around 10% of cases of neuroinvasive disease are fatal. To date there is no effective human vaccine or effective antiviral therapy available to treat WNV infections For this reason, research in this field is rapidly growing. In this article we will review the latest efforts in the design and development of novel WNV inhibitors from a medicinal chemistry point of view, highlighting challenges and opportunities for the researchers working in this field

Lipase Catalysed Kinetic Resolution of Stiripentol

Kinetic resolution of rac-Stiripentol, catalysed by lipase A from Candida antarctica by esterification with vinyl butanoate was performed with an E-value of 24. This allowed isolation of (3S)-Stiripentol with an ee of 86 % and the corresponding (3R)-butanoate with an ee of 87 %. Enzymatic hydrolysis of the ester product gave (3R)-Stiripentol with 94 % ee

Discovery of novel thiazolyl-pyrazolines as dual EGFR and VEGFR-2 inhibitors endowed with in vitro antitumor activity towards non-small lung cancer

New series of thiazolyl-pyrazoline derivatives (7a-7d, 10a-10d and 13a-13f) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds 10b and 10d exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC50 = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC50 = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds 10b and 10d displayed pronounced efficacy against A549 (IC50 = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC50 = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that 10b and 10d were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds 10b and 10d induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells