Synthesis of azetidines, γ-lactams, fused furan bispyrrolidines and 2-pyrazolines: towards medical application

Azetidines are important class of heterocyclic organic compounds in drug discovery and natural product synthesis. Several natural products and pharmaceuticals are containing azetidine precursors such as, penaresidin and Azelnidipine. Iodine mediated cyclisation of homoallylamines were found to furnish iodoazetidines at 20 °C and further reaction with amine nucelophiles afforded aminoazetidines in high yields. The cyclisation of various homoallylamines which different substitution patterns using molecular iodine to furnish new classes of compounds with interesting biological applications were studied. The iodocyclisation of 3-methyl substituted homoallylamine were found to deliver γ-lactam compound in moderate yield as a mixture of diastereoisomers, the reaction conditions were optimised, and the separation into single diastereoisomers and modification in to pyrrolidine ring were investigated. The tricyclic furan bispyrrolidines were obtained in relatively low yields when 3-phenyl substituted homoallylamines were cyclised using the same strategy. The cyclisation of homoallylhydrazines to deliver pyrazoline compounds in high yield was studied in detail. Finally, the biological activity of some of the synthesised compounds were investigated in zebrafish embryo developmental assays and showed intriguing biological responses. Some of the synthesised compounds were sent to Syngenta and Lilly Company for further investigation

Alterations in some Physiological and Inflammatory Markers in Iron-Deficient Obese Adults in the Kurdistan Region, Iraq

Background: Iron homeostasis is crucial to many physiological functions in the human body, such as cellular activity, erythropoiesis, and the innate immune response. Iron deficiency anemia may occur from obesity's ability to disturb iron homeostasis. Obesity may be seen as a pre-inflammatory condition with mild, ongoing systemic inflammation. Additionally, an increase in hepcidin levels by chronic inflammation causes iron insufficiency in obese people. For this reason, this current experiment is designed to investigate the iron profile and some hematological and inflammatory parameters in obese adults in the Kurdistan region-Iraq. Subjects and Methods: The cross-sectional study was designed within the context of a medium private laboratory with participants being common people involved, 200 adults participated in this study and were allocated into two groups according to BMI (control group (BMI ≤ 29.9): N=100 and obese group (BMI >30): N=100). Oxygen saturation (SpO2) and pulse rate were assessed. Blood sera (once) was obtained for iron profiles (s. Iron, Ferritin, Hepcidin) and inflammatory levels (c-reactive protein (CRP), interleukin 6 (IL-6)). Results: Our findings highlighted that all inflammatory markers increased significantly in the obese groups in both sexes and a positive correlation with BMI and a significant decrease in iron in the obese group. Conclusions: This research reveals that hepcidin levels in obese adult people contribute to the development of iron deficiency anemia due to increased inflammation

Assessment of Medication Use by Publics in Sulaimani Province

Drug uses is a multi-step process starting from consulting doctor, prescribing, ordering and using via individual either public or healthcare staff for therapeutic reasons. This process can be problematic for several reasons, especially in developing countries due to easily access to medications, self-diagnosis and people recommendation for certain cases. The aims of the present study were to assess the practice and attitude of medication uses and the knowledge about medication advantage and their risks by publics in Sulaymaniyah province. Then to build correlations between demographic characteristics and medication uses, in order to show the main impact of widely used medication on public health status. Finally, to provide community with statistical data about the level of knowledge, attitude and practice KAP in this region. The overall six hundred participant from the average of ten locations between governmental and privates hospitals and pharmacies as well as clinics were selected from central city and towns for data collection. The majority of participants were public from different background. The present study concluded that the 60 percentage of the participant were lack of adequate knowledge about the ability for differentiation between analgesic and antibiotic medications. The results of the current study showed inappropriate practices and attitudes that contribute to increasing health risks. It is also found that 72 percentage of participant who use prescription only drugs such as antibiotics can be possibly stopped after situation disappeared. This study also investigated several reasons for inappropriate practice, such as wrong believes with irregular consumption of medications, illiteracy, poor health services in terms of pharmacies and healthcare staff as well as easy access to most of the types of medications. Therefore, effort by governmental authorities is urgent toward reducing the risk of the situation, and negative consequences regarding inappropriate practice toward patient care in the region

γ-Lactams and furan bispyrrolidines via iodine mediated cyclisation of homoallylamines

1,3,5-Substituted pyrrolidin-2-ones were synthesisedviaan iodine mediated cyclisation of 3-methyl substituted homoallylamines in good to excellent yield, as mixtures of diastereoisomers. Furan bispyrrolidines were formed as single diastereoisomers when 3-phenyl homoallylamines were employed in an analogous reaction.</p

Azetidines Kill Multidrug-Resistant <i>Mycobacterium tuberculosis</i> without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values &lt;10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies. </p

Prevalence and Molecular Characterization of <i>Echinococcus granulosus</i> Sensu Lato Eggs among Stray Dogs in Sulaimani Province—Kurdistan, Iraq

The main goal of this study was to estimate the prevalence of Echinococcus granulosus among stray dogs, as well as its potential impact on the environmental contamination in the Kurdistan-Iraq using microscopic examination and the Copro-PCR method. The presence of taeniid eggs was recorded in 400 dog faeces collected from the four different regions in the Sulaimani Governorate. The parasite eggs were recovered from fresh and aged faecal samples of the dogs using two isolation techniques, a flotation method (Sheather’s solution, modified; specific gravity: d = 1.27) and a sedimentation method (formal-ether) in which the sediments from dog faeces were collected. Both methods were used for Copro-PCR to detect the presence of Echinococcus species egg through DNA using common primers designed to amplify a partial gene of cytochrome oxidase subunit 1 (COX1). The results of the microscopic examination showed a higher prevalence rate, i.e., 97 (24.25%) of E. granulosus among stray dogs generally in Sulaimani Governorate. The prevalence of E. granulosus among stray dogs according to the district area was 40, 24, 23, and 20.8% in Rzgari, Kalar, Sulaimani, and Halabja, respectively. The positive samples (n = 50) were selected for molecular confirmation, the DNA was extracted from the sediment of the positive samples and 40 (80%) samples were successfully amplified by polymerase chain reaction. The sequences show that all samples belong to the Echinococcus granulosus sensu lato (G1–G3), with slight genetic variation. It was concluded that the sediment of dog faeces can be used for DNA extraction, which is a new method that increases the sensitivity of the test, and the amount of DNA yield would be higher than the routine method, which directly uses faeces of the dogs. In addition, the molecular diagnosis was more sensitive than the microscope examination for the presence of E. granulosus eggs. The prevalence of E. granulosus in both the final hosts and the intermediate hosts must be regularly monitored

Synthesis of azetidines and pyrrolidines via iodocyclisation of homoallyl amines and exploration of activity in a zebrafish embryo assay

Room temperature iodocyclisation of homoallylamines stereoselectively delivers functionalised 2-(iodomethyl)azetidine derivatives in high yield. Increasing reaction temperature from 20 °C to 50°C switches the reaction outcome to realise the stereoselective formation of functionalised 3-iodopyrrolidine derivatives. It was shown that these pyrrolidines are formed via thermal isomerisation of the aforementioned azetidines. Primary and secondary amines could be reacted with iodomethyl azetidine derivatives to deliver stable methylamino azetidine derivatives. With subtle changes to the reaction sequences homoallyl amines could be stereoselectively converted to either cis- or trans-substituted 3-amino pyrrolidine derivatives at will. The stereochemical divergent synthesis of cis and trans substituted pyrrolidines supports an ion part, aziridinium, isomerisation pathway for azetidine to pyrrolidine isomerisation. Six azetidine derivatives were probed in a zebrafish embryo developmental assay to detect potential biological effects through the analysis of morphology and motility behaviour phenotypes. The range of effects across the probed molecules demonstrates the suitability of this assay for screening azetidine derivatives. One of the probed molecules, rac-(((cis)-1-benzyl-4-phenylazetidin-2-yl)methyl)piperidine, exhibited particularly interesting effects in the developmental assay presenting with hypopigmentation and reduced circulation amongst others. This shows that the zebrafish embryo provides a fast, sensitive and effective way to screen new compounds and in the future in combination with existing in vivo and in vitro assays it will become an integral part in drug discovery and development

Azetidines Kill Multidrug-Resistant <i>Mycobacterium tuberculosis</i> without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies

Azetidines Kill Multidrug-Resistant <i>Mycobacterium tuberculosis</i> without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies