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In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC50 values) and moderate 15-LOX inhibitor (micromolar IC50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors.

TB continues to be a leading health threat despite the availability of powerful anti-TB drugs. We report herein the design and synthesis of various hybrid molecules comprising pyrazine scaffold and various formerly identified anti-mycobacterial moieties. Thirty-one compounds were screened in vitro for their activity against Mycobacterium Tuberculosis H37Rv strain using MABA assay. The results revealed that six compounds (8a, 8b, 8c, 8d, 14b and 18) displayed significant activity against Mtb with MIC values ≤ 6.25 µg/ml versus 6.25 µg/ml for pyrazinamide. The most active compounds were then assessed for their in vitro cytotoxicity against PBMC normal cell line using MTT assay and showed SI > 200. Several in silico studies have been carried out for target fishing of the novel compounds such as shape-based similarity, pharmacophore mapping and inverse docking. Based on this multi-step target fishing study, we suggest that pantothenate synthetase could be the possible target responsible for the action of these compounds. The most active compounds were then successfully docked into the active site of pantothenate synthetase enzyme with favorable binding interactions. In addition, in silico prediction of physicochemical, ADMET and drug-like properties were also determined indicating that compounds 8b, 8c and 8d are promising candidates for the development of new anti-TB agents with enhanced activity and better safety profile.

Intravenous recombinant tissue-plasminogen-activator (rtPA) and mechanical-thrombectomy (MT) are currently the only approved treatments for acute ischemic stroke. Their effectiveness was demonstrated in several clinical trials, and is therefore standard of care. Pregnant women were not included in these studies and consequently the effectiveness and safety in this group are unclear. We present a rare case of a patient in the third-trimester of pregnancy that underwent MT. A 29-year-old woman of 39 weeks' gestation presented with left facial-paresis, hemiparesis, and neglect. Her CT-Angiogram showed a large occlusive thrombus within the right M1-M2 segments. During pregnancy she had developed thrombocytopenia. There was initial treatment decision dilemma. In view of her history of thrombocytopenia, there was concern about administering rtPA due to the risk of bleeding. As the thrombus was large, rtPA may also be ineffective. MT was proposed by the Stroke Physician as the preferred treatment option. A concern from the Interventional-Radiologist was the risk of exposure to radiation and contrast agents. As the patient had a disabling stroke at a young age, decision was made to proceed with MT which started 141 minutes after symptom onset. The clot was aspirated without complications. Final check angiogram showed complete resolution of flow within the right middle cerebral artery territory. The patient underwent elective uncomplicated Caesarean-section 5 days later delivering a healthy new born. Severe stroke in pregnancy is rare, but has grave consequences for both mother and infant. Timely decision-making is crucial. Our case demonstrates that MT can be provided safely and effectively in the third trimester of pregnancy.