QSAR analysis of salicylamide isosteres with the use of quantum chemical molecular descriptors

Quantitative relationships between the molecular structure and the biological activity of 49 isosteric salicylamide derivatives as potential antituberculotics with a new mechanism of action against three Mycobacterial strains were investigated. The molecular structures were represented by quantum chemical B3LYP/6-31G* based molecular descriptors. A resulting set of 220 molecular descriptors, including especially electronic properties, was statistically analyzed using multiple linear regression, resulting in acceptable and robust QSAR models. The best QSAR model was found for Mycobacterium tuberculosis (r(2) = 0.92; q(2) = 0.89), and somewhat less good QSAR models were found for Mycobacterium avium (r(2) = 0.84; q(2) = 0.78) and Mycobacterium kansasii (r(2) = 0.80; q(2) = 0.56). All QSAR models were cross-validated using the leave-10-out procedure

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

Influence of Lipophilicity on the Antimycobacterial Activity of the Hydrochlorides of Piperidinylethyl Esters of Ortho-Substituted Phenylcarbamic Acids

A series of 14 hydrochlorides of piperidinylethyl esters of orthosubstituted phenylcarbamic acids were evaluated for in vitro antimycobacterial activity against the strains of Mycobacterium tuberculosis, Mycobactenum kansasii and Mycobactenum avium. In vitro antimycobacterial activrty becomes higher with increasing hydrophobicity of the substituents. The alkoxy group is not necessary in order for the basic ethyl esters of phenylcarbamic acids to display antimycobacterial activity