Dihydrofolate reductase (DHFR) is an important enzyme for de novo synthesis of nucleotides in Plasmodium falciparum and it is essential for cell proliferation. DHFR is a well known antimalarial target for drugs like cycloguanil and pyrimethamine which target its inhibition for their pharmacological actions. However, the clinical efficacies of these antimalarial drugs have been compromising due to multiple mutations occurring in DHFR that lead to drug resistance. In this background, we have designed 22 s -triazine compounds using the best five parameters based 3D-QSAR model built by using genetic function approximation. In-silico designed compounds were further filtered to 6 compounds based upon their ADME properties, docking studies and predicted minimum inhibitory concentrations (MIC). Out of 6 compounds, 3 compounds were synthesized in good yield over 95% and characterized using IR, 1HNMR, 13CNMR and mass spectroscopic techniques. Parasitemia inhibition assay was used to evaluate the antimalarial activity of s -triazine compounds against 3D7 strain of P. falciparum. All the three compounds (7, 13 and 18) showed 30 times higher potency than cycloguanil (standard drug). It was observed that compound 18 was the most active while the compound 13 was the least active. On the closer inspection of physicochemical properties and SAR, it was observed that the presence of electron donating groups, number of hydrogen bond formation, lipophilicity of ligands and coulson charge of nitrogen atom present in the triazine ring enhances the DHFR inhibition significantly. This study will contribute to further endeavours of more potent DHFR inhibitors.

We evaluated the efficacy of 2-[5-(4-[¹⁸F]fluoroethoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide] ([¹⁸F]FEBMP) for positron emission tomography (PET) imaging of translocator protein (18 kDa, TSPO). Dissection was used to determine the distribution of [¹⁸F]FEBMP in mice, while small-animal PET and metabolite analysis were used for a rat model of focal cerebral ischemia. [¹⁸F]FEBMP showed high radioactivity uptake in mouse peripheral organs enriched with TSPO, and relatively high initial brain uptake (2.67 ± 0.12% ID/g). PET imaging revealed an increased accumulation of radioactivity in the infarcted striatum, with a maximum ratio of 3.20 ± 0.12, compared to non-injured striatum. Displacement with specific TSPO ligands lowered the accumulation levels in infarcts to those on the contralateral side. This suggests that the increased accumulation reflected TPSO-specific binding of [¹⁸F]FEBMP in vivo. Using a simplified reference tissue model, the binding potential on the infarcted area was 2.72 ± 0.27. Metabolite analysis in brain tissues showed that 83.2 ± 7.4% and 76.4 ± 2.1% of radioactivity was from intact [¹⁸F]FEBMP at 30 and 60 min, respectively, and that this ratio was higher than in plasma (8.6 ± 1.9% and 3.9 ± 1.1%, respectively). In vitro autoradiography on postmortem human brains showed that TSPO rs6971 polymorphism did not affect binding sites for [¹⁸F]FEBMP. These findings suggest that [¹⁸F]FEBMP is a promising new tool for visualization of neuroinflammation.

Translocator protein (TSPO, 18 kDa) is an evolutionary, well-preserved, and tryptophan-rich 169-amino-acid protein which localizes on the contact sites between the outer and inner mitochondrial membranes of steroid-synthesizing cells. This mitochondrial protein is implicated in an extensive range of cellular activities, including steroid synthesis, cholesterol transport, apoptosis, mitochondrial respiration, and cell proliferation. The upregulation of TSPO is well documented in diverse disease conditions including neuroinflammation, cancer, brain injury, and inflammation in peripheral organs. On the basis of these outcomes, TSPO has been assumed to be a fascinating subcellular target for early stage imaging of the diseased state and for therapeutic purposes. The main outline of this Review is to give an update on dealing with the advances made in TSPO PET tracers for neuroinflammation, synchronously emphasizing the approaches applied for the design and advancement of new tracers with reference to their structure-activity relationship (SAR).