Medicinal chemistry approaches for the discovery of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors as antimalarial agents.

Malaria is a severe human disease and a global health problem because of drug-resistant strains. Drugs reported to prevent the growth of Plasmodium parasites target various phases of the parasites' life cycle. Antimalarial drugs can inhibit key enzymes that are responsible for the cellular growth and development of parasites. Plasmodium falciparum dihydroorotate dehydrogenase is one such enzyme that is necessary for de novo pyrimidine biosynthesis. This review focuses on various medicinal chemistry approaches used for the discovery and identification of selective P. falciparum dihydroorotate dehydrogenase inhibitors as antimalarial agents. This comprehensive review discusses recent advances in the selective therapeutic activity of distinct chemical classes of compounds as P. falciparum dihydroorotate dehydrogenase inhibitors and antimalarial drugs.

Impact of JME on quality of life: Does a well-controlled epilepsy also hamper the psychological wellbeing?

PURPOSE: Epilepsy is a stigmatizing disorder and its diagnosis can have important psychosocial consequences on individuals, severely impacting their quality of life(QOL). There are numerous studies which have seen an adverse impact on the psychosocial aspects of life in patients with intractable epilepsy. The aim of this study was to assess the QOL in adult and adolescent patients with JME, which is largely a well-controlled form of epilepsy. METHODOLOGY: This was a hospital based cross-sectional observational study comprising of 50 JME patients. QOLIE-31-P and QOLIE-AD-48 questionnaires were used to assess QOL in adults & adolescents(11-17 years) respectively. The Mini international neuropsychiatric interview-version 7.0.2 and Brief psychiatric rating scale were used for screening of underlying psychopathology and if, the screening tests were positive then they were further evaluated and classified using DSM V and ICD 10. RESULTS: The mean QOLIE-31-P score was 64.65 ± 15.74. Majority of the adult patients had fair QOL (poor, fair and good QOL scores in 18 %, 54 % and 28 % respectively). Subscale scores in poor category were for the medication effects and pertaining to seizure worry.Among adolescent patients, the mean QOLIE 48 AD score was 69.15 ± 13.13. 50 % had fair QOL. Amongst those with poor QOL, majority of poor scores were for the attitude towards epilepsy. The QOL scores were significantly poorer in patients with uncontrolled seizures. 78 % of the patients had comorbid anxiety and depression, however syndromic psychiatric diagnosis was seen in 10.25 % and 2.56 % for anxiety and depression respectively. Presence of psychiatric symptoms did not influence QOL scores. CONCLUSION: QOL, in well controlled JME, is fair in majority of patients. QOL might improve if seizure worry is addressed and patients are educated about medication effects at the time of initial diagnosis. Vast majority of patients may experience minor psychiatric issues, which do need addressal for formulating a holistic and individualized treatment plan.

Integrated structure-guided computational design of novel substituted quinolizin-4-ones as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors.

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a known drug target for the development of antimalarial agents. Herein, we presented integrated structure-guided computational strategies for the design of novel quinolizin-4-ones as PfDHODH inhibitors. PROCHECK and ERRAT analysis were performed for the validation of co-crystal structures of PfDHODH enzyme bound to the inhibitors available on PDB. Based on the results, PDB ID: 6i55 was selected for further structure-guided in silico studies. Five featured-based pharmacophore model (AADRR) was generated, and validated using GH scoring (0.74) and ROC analysis (0.94). Validated structure-based model was further used as a 3D search query to screen the ZINC database. Retrieved database compounds ZINC00386658, ZINC08439293, and ZINC09089086 were found in agreement with query features based on their highest fitness scores. HTVS, SP and XP docking studies with these retrieved hits demonstrated important interactions (His185. Arg265) with PfDHODH. Mapping of features of the pharmacophore model on these retrieved hits along with the role played by scaffolds and functional groups in docking study helped in the selection of quinolizin-4-one as a main scaffold and different functional groups for the design of novel compounds as PfDHODH inhibitors. In silico ADMET prediction study suggested that designed quinolizin-4-ones are "drug-like" candidates and can be synthesised without too many difficulties. In docking study of newly designed compounds, 8d exhibited the highest docking score of - 12.78 kcal/mol and formed important polar interactions (His185. Arg265) with the PfDHODH. PfDHODH-8d complex showed stable RMSD between 2.5 Å and 3 Å during 100 ns MD simulation study. The RMSD, RMSF and RoG analysis of the PfDHODH-8d complex indicated the absolute stability of the complex. Overall, combined in silico study identified quinolizin-4-ones as selective PfDHODH inhibitors.

The Spectrum of Repetitive Behaviors Associated With Subacute Sclerosing Panencephalitis.

BACKGROUND: Repetitive behaviors refer to a broad class of responses ranging from stereotypic body movements to impulsive/compulsive behaviors. They may be associated with neurological disorders. METHODS: This is a case series of six subacute sclerosing panencephalitis (SSPE) patients who presented with a wide spectrum of repetitive motor behaviors and vocalizations. RESULTS: Repetitive motor behaviors involved the upper limbs in all patients and lower limbs in 3 patients. The repetitive movements in the upper limbs were clapping, finger-clicking, hand rubbing, flailing, and dystonic posturing. In the lower limbs, the repetitive movements were rubbing with the heel, pelvic thrusting with flexion extension of the leg, and foot tapping. The spectrum of vocalizations included palilalia, whistling, grunting with spitting, and pathological crying. Repetitive behaviors were the presenting features in 2 patients. CONCLUSIONS: This case series expands the spectrum of repetitive behaviors seen in neurological disorders associated with brain infections. © 2020 International Parkinson and Movement Disorder Society.

Stereotypies in adults: a systematic review.

Stereotypies are abnormal involuntary non-goal-directed movement patterns or vocalisations which repeat continuously in the same fashion over a period of time and on multiple occasions and are typically distractible. Stereotypies are common in both children and adults, but they are extensively reviewed only in children. There are very few studies, mainly in the form of case reports and case series, focusing on stereotypies occurring in adults as part of different neurological disorders. In adults, stereotypies can be both physiological and pathological. Common physiological stereotypies in adults are leg shaking, face touching, playing with pens or hair, nail biting, hand tapping, foot tapping, and body rocking. Pathological stereotypies in adults are associated with a variety of neuropsychiatric conditions like neurodegenerative disorders, viral encephalitis, autoimmune encephalitis, stroke, psychiatric illness, and drug use. In this review, we focus on the various causes of stereotypic movements in adults, and their pathophysiology, clinical manifestations, and treatment.