Design, synthesis and pharmacological evaluation of novel fused pyrimidine analogues as anticancer agents.

Doctoral Degree. University of KwaZulu-Natal, Durban.Cancer is a multifaceted disease considered as the most serious health burden all over the world. Due to existing of limited anticancer drugs and detrimental side effects, the anticancer research has been challenging. An investigation on identifying novel potential drugs is highly required to treat this serious abnormal cell growth. Advanced potential anticancer drug entrants are crucially required to combat the drawbacks linked with current drugs or line of therapies. Extensive investigations are being carried out on synthetic manipulations of heterocyclic aromatic compounds (purines) for developing efficient and potent anticancer drugs. Besides, these manipulations also offer effective leads for further optimization. Therefore, this project is an effort in detecting a novel and potent anticancer leads based on bioisostere of purines called pyrazolopyrimidines. In this research project we have performed an comprehensive literature survey of structural isomers of pyrazolopyrimidines (pyrazolo[1,5-a]pyrimidine and pyrazolo[4,3-d]pyrimidine) for their synthetic approaches and biological activities with special emphasis on structure-activity relationship (SAR) studies. These SAR studies prompted us to implement the observed studies on one of the structural isomer of pyrazolopyrimidine called pyrazolo[3,4-d]pyrimidine. And further, we have synthesized some novel series of pyrazolo[3,4-d]pyrimidine derivatives with various substituents at C-4 and C-6 positions of the scaffold. A total 71 compounds comprising of phenethyl and pentane hybrids (7-43, Chapter 4), benzoyl hybrids (5a-5h, 6a-6d and 7a-7c, Chapter 5) and lastly phenylcarbamoyl acetamide hybrids (9a-9s, Chapter 6) have been synthesized by molecular hybridization approach as outlined in schemes of respective chapters. The completion of reaction and the purity of novel synthesized compounds were confirmed by chromatographic analysis. All the newly synthesized compounds displayed acceptable analysis for their anticipated structures, which were established based on physicochemical and spectral data (IR, 1 H NMR, 13C NMR and HRMS). All synthesized compounds were primarily evaluated for their in vitro anticancer activities at Laboratory of Growth Regulators, Centre of the Region Hana for Biotechnological and Agricultural Research, Palacky University & Institute of Experimental Botany ASCR, Slechtitelu 27, 78371 Olomouc, Czech Republic. From the systematic analysis of anticancer activity, results obtained following key observations were made. i. Structural isomers of fused pyrimidines have been looked upon for molecular changes in emerging drug like candidates. Pyrazolopyrimidine is a bioisostere of purines has acquired considerable importance due to its diverse, facile and general synthetic methodologies with great medicinal importance. Several analogs of this scaffold have emerged as a promising leads in the design of some novel pharmacologically active compounds with enhanced iii metabolic, pharmacokinetic and pharmacological profiles, representing that there is plenty scope for considering pyrazolopyrimidine as a structural framework for evolving effective leads. ii. Chapter 4: From the 37 novel phenethyl and alkyl pentane pyrazolo[3,4-d]pyrimidine derivatives synthesized and evaluated for CDK2/Cyclin E, Abl kinase inhibitory activity and anti-proliferative activity against K-562 (chronic myelogeneous leukemia) and MCF7 (breast adenocarcinoma) cell lines. From the tested results, compounds 11 (CDK: IC50 = 5.1 µM; Abl: ˃12.5 µM), 8 (CDK: IC50 = 7.8 µM; Abl: ˃25 µM) and 36 (CDK: IC50 = 8.8 µM; Abl: >25 µM) exhibited significant inhibitory activity. Further from this series, most of the synthesized compounds indicated prominent anti-proliferative effects with IC50 value ranging from 19.2 µM to 27.4 µM. Incorporation of monosubstituted phenyl groups at C-4 of the pyrazolo[3,4-d]pyrimidine nucleus had favored for most prominent anticancer activity. iii. Chapter 5: Among the 15 novel benzoyl hybrids synthesized and evaluated, compounds 5a and 6c displayed (CDK2: IC50 = 8.8 µM, 6.8 µM) commendable inhibitory activity and notable anti-proliferative activity ranging from 18.9 µM to 89.3 µM). Presence of heteroatom containing bicyclic moieties at C-4 of the nucleus enhanced both inhibitory and anti-proliferative activity. iv. Chapter 6: Of the 19 novel phenylcarbamoyl acetamide hybrids synthesized and tested, compounds 9a, 9c, 9g, 9m and 9p showed moderate enzymatic inhibitory activity with an IC50 value ˃12.5 µM against both CDK2 and Abl kinases while, remaining compounds of this series could not generate IC50 values due to solubility limit (IC50 = ˃25 µM to ˃100 µM).Professor Neil Koorbanally was acknowledged by the author as his previous supervisor

Consistent Information For IoT In Elegant System With The Hold Up Of Cloud

This adds to the search query for data labels, and is an important way to make all cipher models available in the refrigerator before selling to cloud computing, or perhaps more than any information on select if not development is not fully reliable. We framed our plans by attacking selected key data. We conducted the survey results slowly and appeared on a database of supporting data and data providers. We recognize different actions and keywords in our designs. These words are ideal for files, but they do mean things that people use. In addition, using branding agents and file folders, the component program is suitable for general publishing offices and enjoys user development. Unlike current employees allowed by a new search system, our options can satisfy the process of dismissal and granulation at the same time. Unlike the analysis of historical data, our system allows the search for permission and the use of data to generate data to reset data. Monitoring skills are a clear indication of the level of care in the system and in addition to the number of certified employees. This is why the right to preparation is so important for any prison, for example the year. Our ABKS-UR techniques are designed for the design and extraction of global data in real-world realities, with the ease of reading, with respect to integration

Recognition of Users' Activities using Constraint Satisfaction

Ideally designed software allow users to explore and pursue interleaving plans, making it challenging to automatically recognize user interactions. The recognition algorithms presented use constraint satisfaction techniques to compare user interaction histories to a set of ideal solutions. We evaluate these algorithms on data obtained from user interactions with a commercially available pedagogical software, and find that these algorithms identified users’ activities with 93% accuracy.Engineering and Applied Science

Research on the analytics of traffic pumping in telecommunications via data science using rehabilitated frog leaping algorithm

One kind of telecom crime known as "traffic pumping" occurs when local phone companies artificially overstate the volume of calls flowing into their systems so that they may charge the calling party a greater access fee than their own. Lacking labels for training set makes it difficult to determine whether congestion pumps has occurred. In this study, we suggested a decision-support system based on cluster analysis and decision trees for identifying fraudulent cases. In this study, we use the IBM Telco and Cell2cell datasets. The gathered information can be preprocessed using normalization. When we have collected enough data, we use the rehabilitation frog leaping algorithm (RFLA) to divide up the possible incidents of fraud into distinct groups. Next, we used the cluster participation labels to build a decision tree that led us to the criteria that must be met in order to pursue legal action against the circumstances that raised red flags. Professionals in the field of telecommunications (TC) verify these guidelines in an effort to find a legal remedy against accused offenders. The results are demonstrated and proved the efficiency of the proposed system by comparing it with the conventional techniques

Catching them young: an assessment of hygiene knowledge in government school children in Delhi

Children are recognised as change agents in hygiene promotion. Though numerous efforts are being made to sensitise them on the importance of hygiene it is necessary to gauge their current understanding. For the 2015 Global Handwashing Day, WaterAid India and Society for All Round Development (SARD) conducted quizzes to reinforce the importance of hygiene within schools and recognise children as school health ambassadors and nurture them as change agents between their schools and communities. The quiz helped us analyse the current understanding of the school children on different aspects of hygiene and design targeted interventions needed to further their understanding on the subject. Based on the analysis of the responses of the children to the quiz questionnaire we found that the children from different age groups, classes and gender had different levels of understanding on various aspects of hygiene

Mesenteroaxial volvulus in an adult: time is of the essence in acute presentation

Acute gastric volvulus is an uncommon condition with severe repercussions if untreated in the acute presentation. We describe such a case. We assert that computed tomography (CT) should be the first line of investigatio

Hypertension treatment capacity in India by increased workforce, greater task-sharing, and extended prescription period: a modelling study

Background: The worldwide control rate for hypertension is dismal. An inadequate number of physicians to treat patients with hypertension is one key obstacle. Innovative health system approaches such as delegation of basic tasks to non-physician health workers (task-sharing) might alleviate this problem. Massive scale up of population-wide hypertension management is especially important for low- and middle-income countries such as India. Methods: Using constrained optimization models, we estimated the hypertension treatment capacity and salary costs of staff involved in hypertension care within the public health system of India and simulated the potential effects of (1) an increased workforce, (2) greater task-sharing among health workers, and (3) extended average prescription periods that reduce treatment visit frequency (e.g., quarterly instead of monthly). Findings: Currently, only an estimated 8% (95% uncertainty interval 7%–10%) of ∼245 million adults with hypertension can be treated by physician-led services in the Indian public health system (assuming the current number of health workers, no greater task-sharing, and monthly visits for prescriptions). Without task-sharing and with continued monthly visits for prescriptions, the least costly workforce expansion to treat 70% of adults with hypertension would require ∼1.6 (1.0–2.5) million additional staff (all non-physicians), with ∼INR 200 billion (≈USD 2.7 billion) in additional annual salary costs. Implementing task-sharing among health workers (without increasing the overall time on hypertension care) or allowing a 3-month prescription period was estimated to allow the current workforce to treat ∼25% of patients. Joint implementation of task-sharing and a longer prescription period could treat ∼70% of patients with hypertension in India. Interpretation: The combination of greater task-sharing and extended prescription periods could substantially increase the hypertension treatment capacity in India without any expansion of the current workforce in the public health system. By contrast, workforce expansion alone would require considerable, additional human and financial resources. Funding: Resolve to Save Lives, an initiative of Vital Strategies, was funded by grants from Bloomberg Philanthropies; the Bill and Melinda Gates Foundation; and Gates Philanthropy Partners (funded with support from the Chan Zuckerberg Foundation)

Acute Intrathoracic Gastric Volvulus due to Diaphragmatic Hernia: A Rare Emergency Easily Overlooked

Acute intrathoracic gastric volvulus occurs when the stomach undergoes organoaxial torsion in the chest due to either concomitant enlargement of the hiatus or a diaphragmatic hernia. Iatrogenic diaphragmatic hernia can occur after hiatal hernia repair and other surgical procedures, such as nephrectomy, esophagogastrectomy and splenopancreatectomy. We describe a 49-year-old woman who presented to our emergency department with acute moderate epigastric soreness and vomiting. She had undergone extensive gynecologic surgery including splenectomy 1 year before. The chest radiograph obtained in the emergency department demonstrated an elevated gastric air-fluid level in the left lower lung field. An urgent gastroscopy showed twisted structural abnormality of the stomach body. A computed tomography scan demonstrated the distended stomach, located in the left lower hemithorax through a left diaphragmatic defect. Emergent transthoracic repair was performed. Postoperative recovery was uneventful, and the patient did not experience any pain or difficulty with eating

Delayed diagnosis of intermittent mesenteroaxial volvulus of the stomach by computed tomography: a case report

10.1186/1752-1947-2-343Journal of Medical Case Reports234

SOSAS Study in Rural India: Using Accredited Social Health Activists as Enumerators

Background: Global estimates show five billion people lack access to safe, quality, and timely surgical care. The wealthiest third of the world’s population receives approximately 73.6% of the world’s total surgical procedures while the poorest third receives only 3.5%. This pilot study aimed to assess the local burden of surgical disease in a rural region of India through the Surgeons OverSeas Assessment of Surgical Need (SOSAS) survey and the feasibility of using Accredited Social Health Activists (ASHAs) as enumerators. Material and Methods: Data were collected in June and July 2015 in Nanakpur, Haryana from 50 households with the support of Indian community health workers, known as ASHAs. The head of household provided demographic data; two household members provided personal surgical histories. Current surgical need was defined as a self-reported surgical problem present at the time of the interview, and unmet surgical need as a surgical problem in which the respondent did not access care. Results: One hundred percent of selected households participated, totaling 93 individuals. Twenty-eight people (30.1%; 95% CI 21.0–40.5) indicated they had a current surgical need in the following body regions: 2 face, 1 chest/breast, 1 back, 3 abdomen, 4 groin/genitalia, and 17 extremities. Six individuals had an unmet surgical need (6.5%; 95% CI 2.45%–13.5%). Conclusions: This pilot study in Nanakpur is the first implementation of the SOSAS survey in India and suggests a significant burden of surgical disease. The feasibility of employing ASHAs to administer the survey is demonstrated, providing a potential use of the ASHA program for a future countrywide survey. These data are useful preliminary evidence that emphasize the need to further evaluate interventions for strengthening surgical systems in rural India