ABSTRACT
Plasmodium falciparum dihydrofolate reductase is an important target for antimalarial chemotherapy. The emergence of resistance has significantly reduced the efficacy of the classic antifolate drugs cycloguanil and pyrimethamine. In this paper we report new dihydrofolate reductase inhibitors identified using molecular modelling principles with the goal of designing new antifolate agents active against both wild and tetramutant dihydrofolate reductase strains three series of trimethoprim analogues were designed, synthesised and tested for biological activity. Pyrimethamine and cycloguanil have been reported to loose efficacy because of steric repulsion in the active site pocket produced due to mutation in Plasmodium falciparum dihydrofolate reductase. The synthesised molecules have sufficient flexibility to withstand this steric repulsion to counteract the resistance. The molecules have been synthesised by conventional techniques and fully characterised by spectroscopic methods. The potency of these molecules was evaluated by in vitro enzyme specific assays. Some of the molecules were active in micromolar concentrations and can easily be optimised to improve binding and activity.
ABSTRACT
As a part of our ongoing research to develop novel antitubercular agents, a series of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazoles have been synthesized and tested for antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv strain using the BACTEC 460 radiometric system. A 3D-QSAR study based on CoMFA and CoMSIA was performed on these pyrazole derivatives to correlate their chemical structures with the observed activity against M. tuberculosis. The CoMFA model provided a significant correlation of steric and electrostatic fields with the biological activity while the CoMSIA model could additionally shed light on the role of hydrogen bonding and hydrophobic features. The important features identified in the 3D-QSAR models have been used to propose new molecules whose activities are predicted higher than the existing systems. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antitubercular agents.
Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Quantitative Structure-Activity Relationship , Anti-Bacterial Agents/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Ketones , Models, Chemical , Molecular Conformation , Static Electricity , TemperatureABSTRACT
In breast cancer, the correct evaluation of cancer dissemination is essential to establish prognosis and treatment choices. This study analyses the relationship between circulating levels of soluble VCAM-1 and E-selectin and the presence of circulating cancer cells in breast cancer patients. Plasma levels of VCAM-1 and E-selectin were measured by enzyme-linked immunosorbent assay (ELISA). The presence of circulating cancer cells was diagnosed using a RT nested-PCR assay detecting the cancer specific transcript, epidermal growth factor receptor variant III (EGFRvIII) mRNA. Blood samples were collected from 64 patients divided in three groups: group A of 11 women selected for neoadjuvant chemotherapy; group B of 13 women with metastatic disease and group C, with 40 women having completed their treatment at least one year ago and with no evidence of relapse. The mutant transcript was detected in 45.5% of patients from group A, in 61.5% of patients from group B and in none of the group C patients. For both VCAM-1 and E-selectin, plasma levels increased with disease staging and with the presence of EGFRvIII mRNAin peripheral blood. The differences were statistically significant (p < 0.025) when group C was compared with all patients from group B, with patients from group B with EGFRvIII positive results or with all patients with EGFRvIII positive results. Increased plasma levels of VCAM-1 and E-selectin are associated with advanced stage of breast cancer and with the presence of circulating cancer cells. The combined analysis of these parameters may contribute to a more accurate evaluation of cancer dissemination.
