نطاق التصرف القانوني غير المسجل بنقل ملكية الأراضي في القانون والقضاء الفلسطيني

لا يزال البحث في موضوع العقار والحقوق التي تنشأ عليه من الموضوعات الحيوية والمهمة لدى الباحثين, ويتناول موضوع البحث نطاق التصرف القانوني في الأراضي غير المسجل لدى دائرة تسجيل الأراضي المختصة في فلسطين, ومدى نقل ملكية العقار بمثل هذا التصرف, و توضيح دلالة التصرف القانوني في القوانين المتعلقة بالأراضي المطبقة في فلسطين, وما آثار حول تفسيره من خلافاً قانونياً وقضائياً واسعاً, واتبع الباحث المنهج التحليلي للقوانين المتعلقة بالأراضي و القانون المدني الفلسطيني الجديد رقم (4) لسنة 2012, مع الاسترشاد بما وقف عليه القضاء, وتوصل الباحث لنتيجة هامة, بأن التصرف القانوني في الأراضي المملوكة غير المسجل يعتبر تصرف ابتدائي يصح أن يكون سبباً للمطالبة بالتنفيذ العيني أمام القضاء, ويجوز الحكم له بالتنفيذ العيني للعقد الغير مسجل, وأوصينا بضرورة النص في القانون المتعلق بانتقال ملكية الأراضي سواء كانت أراضي مملوكة أو غيرها, على بطلان جميع التصرفات القانونية واعتبارها باطلة بطلان مطلق, وضرورة التقيد بتسجيل هذه التصرفات أمام دائرة تسجيل الأراضي, وذلك حفاظا على الحقوق وعدم اثارت النزاعات القضائية حول ملكية العقارات, لما لها من أهمية اقتصادية في الدولة.

Evaluation of Synthesized Bis-Aminomethylene Derivatives of Hydroquinone for Anti-Inflammatory, Anti-Pyretic, Anti-Nociceptive, and Gastiric Ulcerogenic Activities in Animal Models

Non-steroidal anti-inflammatory drugs (NSAIDs) have long been the most frequently prescribed drugs in the developed world for the treatment of pain, fever, and inflammation. However, their chronic use is well known to be associated with significant morbidity, particularly in terms of gastric ulceration, bleeding from gastrointestinal tract (GIT), cardiovascular problems and renal complications. The frequency of clinically significant gastrointestinal (GI) side effects and potentially life-threatening toxicity due to NSAIDs is high and causes some patients to desert NSAIDs therapy. Therefore, the challenge still exists for the pharmaceutical industry to develop effective alternatives with enhanced safety profile which will at least maintain their pharmacological properties. Heterocyclic compounds are profusely found in nature and are very important from both therapeutic and economic point of view. In our attempt to discover new and useful agents for treatment of pain, inflammation and pyrexia, we have gathered the two bioactive entities (hydroquinone and moieties) into one compact structure and evaluated their biological activities, which have been found to possess an interesting profile of anti-nociceptive, antipyretic and anti-inflammatory activities with significant reduction in their ulcerogenic effect. The heterocyclic moieties reported here are morpholine, piperidine-4-carboxamide, piperidine and pyrrolidine. This Ph.D. dissertation reports the synthesis and characterization of novel hydroquinone derivatives and their evaluation for different in-vivo biological activities. Hydroquinone derivatives i.e. [2,5-bis(morpholinomethyl)hydroquinone as compound I], [1,1''-((2,5-dihydroxy-1,4-phenylene)bis(methylene))bis(piperidine-4 Abstract xix carboxamide) as compound II], [2,5-bis(piperidinomethyl)hydroquinone as compound III] and [2,5-bis(pyrrolidinomethyl)hydroquinone as compound IV] were synthesized by refluxing a mixture of hydroquinone, paraformaldehyde and the respective moiety (morpholine, piperidine-4-carboxamide, piperidine, pyrrolidine), in a reflux condenser with constant stirring which was assembled on magnetic stirrer. The resulting solution was than cooled while solvent was slowly evaporated at room temperature. The obtained solids were recrystallized three times with ethanol or acetone to obtain pure compounds. Their structures were elucidated using different spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, HRMS (ESI) and elemental analyses. The compounds were then subjected to pharmacological evaluation for in-vivo activities in order to prove that adding the heterocyclic moieties (morpholine, piperidine-4 carboxamide, piperidine and pyrrolidine) into the basic hydroquinone ring structure enhances the pharmacological activities and reduce the side effect (gastric ulceration) associated with traditional NSAIDs. These compounds were screened for their prospective antinociceptive (chemical and thermal induced nociception), anti-inflammatory (carrageenan induced paw edema) and antipyretic (brewer‘s yeast induced pyrexia) activities in comparable doses relative to aspirin. Docking analysis was also conducted for their inhibition capacity towards cyclooxygenase (COX) enzymes. 2,5-bis(morpholinomethyl)hydroquinone as compound I and 1,1''-((2,5-dihydroxy-1,4-phenylene)bis(methylene))bis(piperidine-4 carboxamide) as compound II at doses of 50, 100, 150 mg/kg, significantly attenuated the tonic acetic acid induced and thermally induced nociceptive pain, while 2,5 bis(piperidinomethyl)hydroquinone as compound III and 2,5 bis(pyrrolidinomethyl)hydroquinone as compound IV at doses of 10, 20 and 40 mg/kg, significantly attenuated only the tonic acetic acid induced nociceptive pain. Abstract xx Similarly, all these compounds inhibited the temporal inflammatory reaction during the entire study duration (1-5 h) as well as allay the febrile response with all the tested doses (50, 100 and 150 mg/kg) during 0.5 h, 1 and 1.5 h of study period. These beneficial proclivities were comparable to aspirin, used as a standard. The in silico studies predicted high binding affinity of the hydroquinone derivatives to the active site of the cyclooxygenase 2 (COX-2) enzyme. These compounds were then tested in-vivo for per se ulcerogenicity in aspirin induced pyloric ligation model using biochemical and histological correlative approach. Results of the biochemical findings indicated that, the ulcerative effects were exacerbated in aspirin (150 mg/kg) and compound I (150 mg/kg) treated animals, as confirmed from the biochemical parameters such as lesion score, gastric juice pH, gastric juice volume, free acidity and total acidity. However, these biochemical parameters remained unchanged with 2,5-bis(morpholinomethyl)hydroquinone (100 mg/kg), 1,1''-((2,5-dihydroxy-1,4-phenylene)bis(methylene))bis(piperidine-4 carboxamide), 2,5-bis(piperidinomethyl)hydroquinone and 2,5 bis(pyrrolidinomethyl)hydroquinone (100, 150 mg/kg). Additionally, no gross morphological changes of the gastric mucosa were seen with test compounds and saline control. However, the ulcer spots and red coloration of stomach mucosa were clearly visible in aspirin and compound I [2,5-bis(morpholinomethyl)hydroquinone] treated animals, both at 150 mg/kg. Moreover, the photomicrographs from histopathological analysis of stomach specimen of control and drug treated animals revealed no significant changes. However, aspirin treated rats was characterized by disruption of mucosal layer, edema with increased number of lymphocytes in the sub mucosa along with exudates in the muscularis external layer, while compound I [2,5 bis(morpholinomethyl)hydroquinone; 150 mg/kg] treated rats has shown eradication Abstract xxi of the mucosal layer. As revealed from the results of the ulcerogenicity evaluation, the synthesized compounds possess negligible gastric ulcer propensity in comparison to aspirin. In conclusion, hydroquinone derivatives are designed to overcome the serious side effect such as gastric ulcerogenicity associated with traditional NSAIDs. All available evidences, suggest that the synthesized compounds embrace great promise to become a versatile remedial tool. Their potential antinociceptive, anti-inflammatory and antipyretic properties with minimum ulcerogenic proclivity recommend greater safety compared to traditional NSAIDs. Currently, their evaluation for intended significance in medicine is generally at a preclinical stage. Thus, it is hasty to predict or conclude with confidence what their final position in human therapeutics will be. However, further comprehensive research work on the synthesized derivatives is most warranted in order to develop safe and effective therapeutic agents.