Drug Design, Docking Studies And Synthesis of Certain Coumarinyl Azetidin-2-Ones and Evaluation of their Antimycobacterial Activity

Tuberculosis (TB) is the most common cause of the death from infectious disease world-wide, which affects mainly the poorest countries of the world. Cell wall of Mycobacterium tuberculosis includes peptidoglycans and complex lipids (mycolic acids) which are significant determinant of its virulence. Novel antitubercular drugs are urgently needed because TB remains a global health priority [110]. Coumarin compounds as medicinal drugs have been increasingly attracting special interest due to their potential outstanding contributions in the prevention and treatment of diseases, and the related researches and developments have received an increasing attention to synthetic organic chemists [110]. A great deal of effort has been made directly or indirectly towards the discovery and development of coumarin-based antitubercular drugs and some excellent achievements have been acquired. Azetidinone is an exciting pharmaceutical fragment in drug discovery. The strong activity of the famous antibiotics such as penicillins, cephalosporins, thienamycins, nocardicins, aztreonams as well as carbapenems is attributed to the presence of the 2 -azetidinone ring [110]. Mycobacterium tuberculosis genome has high number of cytochrome P450 enzymes and parallel studies indicated that cytochrome P450 inhibiting azole drugs has potent antitubercular activity. Recent research explains potential drug target on Mycobacterium tuberculosis P450 and provides evidence for roles of selected P450 isoforms in host lipid and sterol or steroid transformations Drug discovery tools help in designing new molecular entities which are safe and effective without consuming much of the research hours. The purpose of the present work was to design and synthesize new azetidine-2-one derivatives containing coumarin moiety in order to explore the extent of their antitubercular activity. The compounds were designed by in silico method using MT-CYP51 as the target molecule.SUMMARY: The present work was focused on the designing of novel azetidin-2-one derivatives with coumarin moiety having antitubercular activity. For this, following approach has been adopted. PHASE I: DRUG DESIGN APPROACH: It involves the following stages: Stage 1: Identification of target Cytochrome P450 lanosterol 14α-demethylase in Mycobacterium tuberculosis (MT-CYP51) was selected as the target enzyme as its inhibition will prevent synthesis of the membrane lipids. This compromises membrane integrity and induces Mycobacterial cell lysis.Stage 2: Lead Identification The lead coumarin was selected based on several literature reviews. 150 compounds including a series of azetidinone, imidazolidinone, thiazolidinone and oxazolidinone derivatives of coumarin were subjected to molecular docking studies. All the compounds were found to have binding energy lesser than that of the standard fluconazole. A series of twelve azetidinone (az31-az42) derivatives were selected from these compounds on the basis of their binding energy. az37 (P1) and az38 (P2) was found to have the least binding energy of -11.28 and - 11.24, respectively. Safety and efficacy of the lead molecules were evaluated by observing the in silico ADME studies and computation of drug like properties. Twelve ligands (N1-6 and P1-6) were subjected to in silico lead optimization. Oral bioavailability was evaluated was evaluated by using Molinspiration server and ADMET data were obtained from Accelry’s Accord for Excel. All the compounds possessed good bioavailability and permeability.CONCLUSION: The present study establishes that computational tools help in minimizing the tedious process of drug discovery and delivers new drug candidate more quickly. Cytochrome P450 lanosterol 14α-demethylase in Mycobacterium tuberculosis (MT-CYP51) was selected as the target and coumarin as the lead, which was optimized based on drug likeness score. The proposed twelve compounds were synthesized and their structures were established based on spectral data. The compounds were evaluated for antibacterial and antimycobacterial activity. The synthesized compounds showed poor to moderate antibacterial activity. Five synthesized derivatives (N2, N6, P3, P4 and P6) showed equipotent antitubercular activity compared to the standards Pyrazinamide and Ciprofloxacin at concentration of 3.12µg/ml. Two synthesized derivatives (P3 and P6) exhibited higher level of antitubercular activity even at a low concentration of 1.6µg/ml. Among the synthesized compounds, 3-phenyl substituted azetidin-2-ones showed promising antimycobacterial activity. Among the synthesized compounds, P3 and P6 can be taken as the lead molecule and acute toxicity studies are to be done on these promising compounds

Micropropagation and conservation of selected endangered anticancer medicinal plants from the Western Ghats of India

Globally, cancer is a constant battle which severely affects the human population. The major limitations of the anticancer drugs are the deleterious side effects on the quality of life. Plants play a vital role in curing many diseases with minimal or no side effects. Phytocompounds derived from various medicinal plants serve as the best source of drugs to treat cancer. The global demand for phytomedicines is mostly reached by the medicinal herbs from the tropical nations of the world even though many plant species are threatened with extinction. India is one of the mega diverse countries of the world due to its ecological habitats, latitudinal variation, and diverse climatic range. Western Ghats of India is one of the most important depositories of endemic herbs. It is found along the stretch of south western part of India and constitutes rain forest with more than 4000 diverse medicinal plant species. In recent times, many of these therapeutically valued herbs have become endangered and are being included under the red-listed plant category in this region. Due to a sharp rise in the demand for plant-based products, this rich collection is diminishing at an alarming rate that eventually triggered dangerous to biodiversity. Thus, conservation of the endangered medicinal plants has become a matter of importance. The conservation by using only in situ approaches may not be sufficient enough to safeguard such a huge bio-resource of endangered medicinal plants. Hence, the use of biotechnological methods would be vital to complement the ex vitro protection programs and help to reestablish endangered plant species. In this backdrop, the key tools of biotechnology that could assist plant conservation were developed in terms of in vitro regeneration, seed banking, DNA storage, pollen storage, germplasm storage, gene bank (field gene banking), tissue bank, and cryopreservation. In this chapter, an attempt has been made to critically review major endangered medicinal plants that possess anticancer compounds and their conservation aspects by integrating various biotechnological tool

Effects of maternal vitamin deficiency on the microstructure of the maternal hippocampus and behavior in offspring

الملخص: أهداف البحث: تلعب التغذية دورا مهما في عمل الدماغ وتطوره. فيتامين ب 6 في شكل فوسفات بيريدوكسال مطلوب للتخليق الحيوي للعديد من الناقلات العصبية. نظرا لأن فيتامين ب 6 لا يتم تصنيعه داخليا، يصبح توفر المصادر الغذائية أمرا ضروريا. بسبب مساهمته في الوظائف العصبية، يؤدي النقص الحاد في فيتامين ب 6 إلى زيادة خطر الإصابة بالاضطرابات النفسية والخرف واضطرابات النمو العصبي. هدفت الدراسة الحالية إلى إنشاء نموذج يعاني من نقص فيتامين ب 6 في حيوانات التجارب وتقييم آثار النمو العصبي في ذريتهم. طريقة البحث: تم استخدام إناث فئران ''س 57 ب ل/6 ج'' عمرها شهرين إلى ثلاثة أشهر في الدراسة. تم تقسيمهم بشكل عشوائي إلى المجموعة الضابطة وفيتامين ب 6 الناقص. تم تغذية المجموعة الضابطة بنظام غذائي منتظم يحتوي على 6 ملغ من فيتامين ب 6 / كغ من النظام الغذائي وتم تغذية المجموعة التي تعاني من نقص فيتامين ب 6 بنظام غذائي مخصص يحتوي على صفر ملغ من فيتامين ب 6 / كغ غذاء لمدة خمسة أسابيع (عدد=6). بعد خمسة أسابيع، تم تقدير فوسفات بيريدوكسال في البلازما. تم تربية الحيوانات لتولد ذرية. تم التضحية بالفئران الأمهات أيضا بعد الفطام، وتم تحديد كمية الخلايا العصبية في قرن آمون باستخدام صبغة الكريسيل البنفسجي. تم تخصيص النظام الغذائي للنسل بعد الفطام حتى عمر شهرين. تم تقييم التعلم والذاكرة باستخدام اختبار متاهة موريس المائية. النتائج: أكدت مستويات البلازما فوسفات بيريدوكسال النقص في المجموعة الناقصة بالمقارنة مع المجموعة الضابطة. أظهرت الخلايا العصبية الهرمية القابلة للحياة في منطقة ''س أ 3'' من قرن آمون فرقا كبيرا بين المجموعة الضابطة والمجموعة الناقصة. أظهر النسل المولود للفئران ذات النقص زيادة كبيرة في زمن الوصول للوصول إلى الربع المستهدف أثناء تجربة المسبار مقارنة بالمجموعة الضابطة. الاستنتاجات: يقلل نقص فيتامين ب 6 من الذاكرة في الفئران وذريتهم، مما يشير إلى أهمية فيتامين ب 6 لكل من وظائف الدماغ وتطوره. يجب القيام بالمزيد من البحث في هذه المعرفة والموقف مع مرور الوقت وتنفيذها الفعلي في الممارسة. Abstract: Objectives: Nutrition plays a critical role in the brain's function and development. Vitamin B6 in the form of pyridoxal phosphate (PLP) is required for the biosynthesis of several neurotransmitters. As vitamin B6 is not endogenously synthesized, the availability of dietary sources becomes imperative. Due to its contribution to neurological functions, severe vitamin B6 deficiency leads to an increased risk of psychiatric disorders, dementia, and neurodevelopmental disorders. This study aimed to establish a vitamin B6-deficient model in experimental animals and assess the neurodevelopmental effects in their offspring. Methods: Two- to three-month-old female C57BL/6J mice were used in the study. They were randomly divided into control and vitamin B6-deficient groups. The control group was fed a regular diet containing 6 mg vitamin B6/kg and the vitamin B6-deficient group was fed a customized diet containing 0 mg vitamin B6/kg, for 5 weeks (n = 6). After 5 weeks, plasma PLP was assessed. The animals were bred to generate offspring. The dams were killed following weaning, and the hippocampal neurons were quantified using cresyl violet staining. The offspring were assigned the respective diet post-weaning up to 2 months of age. Learning and memory were assessed using the Morris water maze test. Results: The plasma PLP levels confirmed the deficiency in the deficient group compared to the control group. The viable pyramidal neurons in the cornu ammonis 3 (CA3) region of the hippocampus showed a significant difference between the control and deficient groups. Offspring born to deficient dams showed a substantial increase in latency to reach the target quadrant during the probe trial compared to the controls. Conclusion: Vitamin B6 deficiency reduces memory in dams and their offspring, suggesting the importance of vitamin B6 for both brain function and development

Need and Viability of Newborn Screening Programme in India: Report from a Pilot Study

India, a country with the second largest population in the world, does not have a national newborn screening programme as part of its health policy. With funding support from the Grand Challenges Canada, a pilot newborn screening programme was implemented for the Udupi district of South India to study the need and viability of a national programme in India. Six disorders were selected for the study based on the availability of funding and recommendation from pediatricians in the district. Here, we report the observed incidence during the study. A cost-effectiveness analysis of implementing newborn screening in India was performed. It is evident from our analysis that the financial loss for the nation due to these preventable diseases is much higher than the overall expenditure for screening, diagnosis, and treatment. This cost-effectiveness analysis justifies the need for a national newborn screening programme in India