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

Similarity approach to QSAR Application to antimycobacterial benzoxazines.

Abstract The antimycobacterial activity in six series of substituted 3-phenyl-2H-benzoxazine-2,4(3H)-dithiones and 3-(phenyl)-4-thioxo-2H-benzoxazine-2,4(3H)-diones has been studied using a quantum molecular similarity approach. The approach is based on the use of fragment self-similarity measures as new universal molecular descriptors applicable for the design of novel theoretical QSAR models. Using this approach it was possible to show that while traditional QSAR models were able to describe the activity only within each of the six sets of studied molecules individually, the proposed approach is much more general and a single universal QSAR model describing the activity of all the 39 studied molecules in all the studied series together was built. The replacement of the oxo group by the thioxo group in position 4 on the benzoxazine ring of the antitubercular 3-(phenyl)-2H-benzoxazine-2,4(3H)-diones increases the activity, as well as the similar replacement in position 2

(E)-4-Hy­droxy-N′-(4-hy­droxy-3-meth­oxy­benzyl­idene)benzohydrazide

In the title compound, C15H14N2O4, the N=C double bond has an E configuration. The two benzene rings make a dihedral angle of 28.59 (6)°. In the crystal, mol­ecules are linked into a three-dimensional network by inter­molecular N—H⋯O, O—H⋯O and C—H⋯O hydrogen bonds and stabilized by weak C—H⋯π inter­actions

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