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Dihydropyrimidines As Potential Drug Candidates, Design, Synthesis, Bioevaluation and Computational Studies

Thesis Info

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Author

Rashid, Umer

Program

PhD

Institute

Quaid-I-Azam University

City

Islamabad

Province

Islamabad.

Country

Pakistan

Thesis Completing Year

2010

Thesis Completion Status

Completed

Subject

Chemistry

Language

English

Link

http://prr.hec.gov.pk/jspui/handle/123456789/696

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676725906315

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Present work refers to the design, synthesis, bioevaluation and computational studies of multifunctionalized dihydropyrimidines (DHPMs) known to possess immense pharmacological activities. A series of DHPM derivatives were synthesized by different strategies. In the first strategy, one pot Biginelli reaction was carried out using three building blocks (i.e. aryl aldehydes, 1,3-dicarbonyl compounds and diamino compounds). Hence three different types of DHPMs namely 4-aryl-3,4- dihydropyrimidine-2-ones (1-44), 4-aryl-3,4-dihydropyrimidine-2-thiones (45-69) and 2-amino-1,4-DHPMs (70-79) were synthesized. Through this strategy diversity was introduced at N1, C2, C4, C5 and C6 positions of pyrimidine nucleus. Moreover, keeping in view the difficulties during the synthesis of DHPM via Biginelli three component reaction, the conditions were optimized by doing these reactions through different modes such as sonication, microwave irradiation, as well as through conventional heating. Excellent yields without any side products were obtained under mild reaction conditions under sonication using a cheap catalyst i.e. SnCl 2 . Based on a simple nucleophilic displacement scheme, another set of 2-aminopyrimidines (83-87) was also synthesized. The second strategy involved modification of different functionalities of DHPM nucleus synthesized previously through one pot strategy. This led to introduction of different diversity elements farther at C5 and C6 positions leading to pyrimidines 88-92. Besides synthesizing a variety of pyrimidines, partial synthesis of ispinesib (a well known KSP inhibitor) was carried out via two routes with a view to optimize the reaction conditions and yield of the rate limiting step each of the two synthetic strategies. Since the synthesized dihydropyrimidines are anticipated to have important pharmacological properties, therefore, all these compounds were subjected to in vitro screening for studying their potential as urease inhibitors, xanthine oxidase inhibitors, thymidine phosphorylase inhibitors, potato disc tumor inhibitors and as antiglycation agents. Compound 53 was found to have very strong potential as urease inhibitor and may serve as a lead for developing into antiulcer drug. iiiIn silico studies were also carried out on the most active compounds identified in different bioassays by doing molecular docking and pharmacophore matching. Furthermore, in silico designing of DHPM based KSP, urease and thymidine phosphorylase inhibitors was carried out with a view to develop novel KSP, urease and TP inhibitors.
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خان الخلیلی بازار

خان الخلیلی بازار

مسجد حسین کے باہر دالان میں بڑی تعداد میں ریستوران موجود ہیں جہاں کھلی فضا میں سیکڑوں میز اور کرسیاں لگیں تھی ۔چند مصری نوجوان گٹار بجا رہے تھے باقی لوگ محظوظ ہو رہے تھے۔نماز کے وقت موسیقی بند تھی ۔دکتور محمود نے کہا یہ ذہنی ہم آہنگی مصری قوم کا خاصہ ہے وہ ایک دوسرے کو بہ زور نہیں روکتے ۔مذہب اور محبت ہم مصریوں کی گھٹی میں ہے مگر ہم اس کے ذریعے ایک دوسرے کوجنت یا جہنم رسید نہیں کرتے ۔ہم جیو اور جینے دو کے اصولوں پر زندگی گزارتے ہیں ۔محمود کی گفتگو میرے دل میں ترازو ہو رہی تھی ۔میری فکر جیو اور جینے دو کے آفاقی اصول کو پاکستانی معاشرے میں ٹٹول رہی تھی ،مگر میری یہ تلاش بے سود تھی ۔مذہبی دھڑے بندیوں ،قوم پرستی ،لسانی تفاوت ،علاقائی بغض اوپر سے حکمران طبقے کی اس ملک اور عوام کے ساتھ چیرہ دستیوں نے پاکستانی معاشرے سے ان دونوں اصولوں کو ناپید کر دیا ہے ۔ مسافر اس سماجی اور مذہبی تخریب پر اپنی سوچوں میں غلطاں تھا جو نائن الیون کے بعد پاکستانی سماج میں انتہا کو پہنچی کہ اس دوران چہل قدمی کرتے کرتے ہم مسجد حسین سے اچھا خاصا فاصلہ طے کر چکے تھے اچانک دکتور محمود نے کہا کہ ہم خان الخلیلی بازار میں کھڑے ہیں ۔فکری پرواز سے زمینی حقائق کی طرف پلٹے تو اپنے آپ کو ایک تنگ مگر مصروف بازار میں پایا ۔چودھویں صدی کے اواخر میں ترک عثمانی دور میں بننے والے اس بازار کا پرانا نام ’’ترکی بازار تھا ‘‘جو بعد میں خان الخلیل کے نام سے مشہور ہوگیا ۔مجھے اس بازار میں لاہور کی انار کلی اور بنکاک کی نانا سٹریٹ کی شبیہ نظر آئی جہاں ہجوم کی حالت یہ تھی کہ ’’نظر چرا کے...

أهمية ثقافة الحوار في الإسلام وجهود المملكة العربية السعودية في نشرها

This is the unique quality of Islam that it respects all the religions. It strictly opposes the preaching of religion based on enforcement, power, misconduct, and discrimination and promotes the culture of dialogue to create an atmosphere of harmony. In this way, it emphasis upon the trends of mutual understanding and cooperation. Allah Almighty has directed it because commonalities on dialogue the start to (صلى الله عليه وسلم) Prophet Holy enhances the interfaith harmony. This research work discusses the importance of culture of dialogue in Islam and highlights the efforts of the KSA in disseminating and promoting that culture at national, regional and international levels. It also refers to the efforts exerted by official and non-official Saudi institutions in advocating dialogue and rapprochement between sects in different societies, promoting peaceful coexistence among different religions and civilizations, and activating conferences and scientific seminars that discuss dialogue and peaceful coexistence. In this research, I used the deductive analysis methodology and concluded that the Kingdom of Saudi Arabia serves Islam by: -Opening the horizons of communication and exchange of knowledge with the other in order to provide a true picture of Islam. -Working to promote the real teachings of Islam in terms of tolerance and passion. -Cooperating in spreading security, peace, virtuous values and building a global system of ethics.

Effects of Thyroid Profile Changes on the Biochemical Makers of Bone, Liver and Renal Function in Non Pregnant Women of Khyber Pakhtunkhawa, Pakistan

This hospital based cross sectional study was conducted from 01 March 2014 to 31 March 2015 in Khyber Teaching Hospital (KTH), a tertiary care hospital in Khyber Pakhtunkhawa (KP) province of Northern Pakistan. The study group comprises of 259 non pregnant women in the age group of 18-75 years. Informed consent was sought from each patient and all human dignity was respected throughout the study period in accordance with the international norms involving human as an experimental subjects. 5 mL of fresh venous blood (fasting sample) was taken from each patient. It was divided into two portions- one portion was used for the determination of thyroid profile markers by Elisa methods and the other portion was used for the determination of serum alkaline phosphatase, calcium, Zinc, urea, creatinine, SGPT and SGOT level on autoanalyser (Erbamannhein chemistry autoanalyser, Germany) by using Erba kits and Standard protocols. After the determination of thyroid profile status, patients having normal thyroid profile (n=54, TSH≤6.0, normal T3 and T4 levels) were taken as controls.While the hypothyroid patients (n=96) and hyperthyroid group (n=109) constituted the study group.The patients in the hypothyroid groups were further sub divided into Sub clinically hypothyroid (Sh) (n=48) and Overtly hypothyroid (Oh) (n=48). Similarly the patients in hyperthyroid groups were also subdivided into Overtly Hyperthyroid (OH) (n=58) and Sub clinically Hyperthyroid (SH) (n=51). Purposive sampling method was employed for the collection of the relevant data. The total no of patients who met the purpose of the study were 259. The data about age, BMI and all the required biochemical parameters for each patient was collected on a well-designed data entry form. The data so obtained was statistically analyzed using SPSS for windows 21.0 software and Microsoft Excel. Values were reported as mean ± standard error of mean. Pearson’s correlation of the data was also carried out to look for association between variables. A, p value of < 0.05 was considered to be significant. The mean age of patients in the control group (N) was 42.15 ± 1.86 years, 46±1.38 years for Overtly hypothyroid (Oh), 45.97±1.93 years for Sub clinically hypothyroid (Sh), 49.74±1.62 years for Overtly Hyperthyroid (OH) and 48.94±1.87 years for the Sub clinically Hyperthyroid (SH).The control group were 54, of which 61.11% (33) were Menopausal (M, age below 45 years), 18.52% (10) were Early Post-Menopausal (EPM, age 45-50 years) and 20.37% (11) were Late Post-Menopausal (LPM, age above 50 years). The %age of M, EPM and LPMin the Oh (48) and Sh (48) group were, 54.16%(26), 12.5%(06), 33.83%(16) and 45.83%(22), 22.92% (11), 31.25%(15) respectively. Similarly the %age of M, EPM and LPM in the OH (58) and SH(51) were 34.48% (20), 27.58%(16), 37.93%(22)and43.14%(22), 07.84%(04), 49.07%(25) respectively. The mean serum level of TSH was found to be lowest in OH group (0.17±0.01µIU/ mL) and highest in the Oh group (25.89±2.86µIU/ mL). Serum T3 level was highest in OH group (2.37±0.01ng/mL) and lowest in Oh group (0.94±0.09ng/mL). Highest serum T4 level was found for OH group (12.07±0.46µg/ dL) and lowest in Oh group (4.30±0.28µg/ dL). Mean serum creatinine was highest in N group (1.47±1.25 mg/dL) as compared to OH (1.29±0.01 mg/dL) and SH group (1.34±0.15 mg/dL). Serum Urea level was found elevated in OH (35.35±1.75 mg/dL) and SH (32.98±1.63 mg/dL) as compared to N group (32.60±1.22 mg/dL). Serum creatinine showed positive relation with TSH, in all the study groups, negative relation with T3 in the N group and OH and positive in SH group. Serum creatinine showed a significant positive correlation with TSH in the OH group (p= 0.05). Serum creatinine showed a significant negative correlation with T3 in the N group (p= 0.05). No significant correlation with T4 was found either for creatinine or Urea in any of the study groups. A minor decrease in the serum creatinin level in the Oh (1.10mg/dL) and Sh group (1.18 mg/dL) was found as compared to N group (1.47mg/ dL). Serum urea was found to be slightly decreased in the Sh group (23.22 mg/dL) as compared to N group (32.60mg/dl) and Oh group (30.11mg/dL). A very significant positive correlation was found between Serum creatinine and T3 in the Sh group (p= 0.005) and significant negative correlation with T3 in the N group (p= 0.05). Urea was significantly negatively correlated with TSH in Sh group (p= 0.05). Mean Serum Calcium was highest in OH group (9.80±0.90 mg/dL) and lowest in Oh group (8.95±0.10 mg/ dL). Serum total alkaline phosphatase was found to be maximum in N group (159±7.61 U/L) and minimum in Sh group (128±6.42 U/L). There were no significant differences in the Serum Zinc level of all the diseased groups. Calcium showed significant positive correlation with TSH in Oh (p=0.01) and OH (p=0.04). Serum Calcium was significantly negatively correlated with T3 in OH (p=0.01). Serum alkaline phosphatase was significantly negatively related with T4 in OH (p=0.01). Serum Zn showed a very significant positive correlation with T3 in SH (p=0.02). Significance differences were found in the SGPT and SGOT level in all the five groups. SGPT level was found to be 33.14±2.98 in OH, 29.50±1.69 in SH group as compared to 29.69±3.28 IU/L in N group. SGOT level was 33.70±5.12 IU/L in N group, 30.68±2.7 in OH group and 30.38±2.6 IU/L in SH group. Avery significant positive correlation was found between SGOT and TSH in the N group (p =0.002). Avery significant positive correlation was also found between BMI and T3 in N group and OH group (p =0.01). SGPT level was found to be 24.35±1.11 IU/L in the Oh, 16.85±0.55 IU/L in Sh as compared to 29.69±3.28 IU/L in N group. SGOT level was 33.70±5.12 IU/L in N group 23.65±1.22 IU/L in Oh group and 17.86±0.98 IU/L in Sh group respectively. SGOT was none significantly negatively correlated with TSH in the Oh and Sh groups. No significant correlation was found between SGPT and thyroid profile markers (TSH, T3 and T4) in any of the study groups. In conclusions, thyroidal dysfunction is a common problem in northern Pakistan affecting women folks more as compared to other gender due to poverty, lack of education, social taboos and lack of health facilities in rural areas.More over there is a lack of adequate amount of iodine in drinking water and iodized salt due to lack of strict quality control. There is a complex interaction between thyroid kidney, liver and bone turnover markers. It was concluded from this study that bones desorption occurs at higher rate in hyperthyroid patients and bone turnover is increased in favor of desorption. Opposite changes are observed in hypothyroid women.Also hyperthyroidism may affect renal function in the long run if left untreated, while hypothyroidism may not affect renal functions in non-pregnant women. It was also concluded from this study that SGOT is directly affected by the change in the serum level of TSH in the normal individual (N). Serum T3 directly affected BMI in N and OH groups. It was also found that hypothyroidism may decrease while Hyperthyroidism may increase the rate of synthesis of liver enzymes.Due to this complex inter play between these vital organs of the body and thyroid hormone, multi system approach should be adopted in the diagnosis of clinical conditions affecting either organs.