Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration.

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC50  = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.

Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy.

Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin-lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1ß (interleukin-1ß), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1ß, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH4CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.

Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor.

Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 µM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint  = 15.6 µl/min/mg; T1/2  = 113.2 min) with solubility of 4.82 µM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.

Role of minimally invasive glaucoma surgery in the management of chronic open-angle glaucoma.

To compare the safety and efficacy of phacoemulsification combined with ab-interno trabeculectomy (Trabectome) and phacoemulsification combined with I-Stent inject in patients with medically uncontrolled primary open-angle glaucoma (POAG). A retrospective comparative case series. 70 eyes of 66 patients completed 2 years follow up after these treatments performed in 2017-2018. 35 eyes of 33 patients underwent combined Phaco-Trabectome (PT); and 35 eyes of 33 patients underwent combined Phaco-I-Stent inject (Pi). Patient demographics and preoperative characteristics are comparable. A 20% drop in IOP was achieved in 27 eyes (77.14%) in PT group and 28 eyes (80%) in Pi group (p = 0.77). Success rate (target IOP achieved and maintained for 2 years) in advance glaucoma was 25% in PT group and 30.7% in Pi group (p = 0.90). In mild to moderate glaucoma, success rate was 85.71% in PT group and 90% in Pi group (p = 0.67). There was no significant difference between two groups with regards to mean reduction in glaucoma medications and complication rates. Trabectome and I-Stent combined with phacoemulsification are equally efficacious and safe for treating patients with medically uncontrolled mild and moderate primary open-angle glaucoma (POAG). However, they are not an effective treatment for patients with advanced glaucoma.

Central serous chorioretinopathy with angioid streaks: a rare combination.

Purpose: This rare case shows the presence of both angioid streaks (AS) and central serous chorioretinopathy (CSC) in the same eye. Methods: A 41-year-old Caucasian male who also has a positive family history of AS was diagnosed with angioid streaks. He was followed for few years, later developed CSC in his good eye. Results: Fundus fluorescein led to the diagnosis of CSC and indocyanine green angiography ruled out the possibility of idiopathic polypoidal choroidal vasculopathy (IPCV). The CSC followed a chronic course of non-resolution and finally half fluence photodynamic therapy was performed. Unfortunately, there was still some deterioration of vision with poor response. Conclusion: There is no known correlation between the two disorders and their presence in one eye has not been reported to our knowledge.

Active iris vascular tufts bleeding successfully treated with argon laser photocoagulation.

PURPOSE: Iris vascular tufts (IVT) are rare biomicroscopic capillary outgrowths from the pupillary margins. Patients are usually asymptomatic until presenting with blurred vision due to spontaneous hyphema or with raised intraocular pressure. CASE REPORT: A 61-year-old woman presented to eye casualty with left eye (LE) blurred vision and discomfort for 1 day. Her external ocular examination was unremarkable and visual acuity was 6/6 in the right eye (RE) and 6/9 in the LE. Biomicroscopic examination revealed a 2-mm hyphema in her LE and bilateral multiple small IVT and active bleeding from IVT at the pupillary margin of the LE at the 5 o'clock position. Diagnosis of LE active bleeding from IVT was made and she underwent argon laser photocoagulation directed at the source of bleeding. The bleeding stopped immediately after the second burn. She was followed up for 3 months; her visual acuity was 6/5 and 6/6 in the RE and LE, respectively, with no further problems. CONCLUSIONS: Iris vascular tufts are benign and recurrent hemorrhages are unlikely. Therefore, definitive argon laser photocoagulation or surgical treatment are reserved to arrest further episodes of hyphema. Our case demonstrates the effective use of argon laser photocoagulation to completely arrest active bleeding from IVT and excellent recovery of hyphema with no further problems for 5 years.