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Title: 3,4,5- Trisubstituted Triazoles: Synthesis, Characterization and Biological Evaluation
Authors: Muzaffar, Saima
Keywords: Physical Sciences
Issue Date: 2021
Publisher: Islamia University, Bahawalpur.
Abstract: Design and production of lead compounds that can be used to prevent, treat and cure diseases is the principal objective of medicinal chemistry. Key role of organic molecules in nature, drug, and technology is well accepted and organic chemist plays as a main driver in pharmaceutical industry in the process of drug discovery. The mushrooming of novel drug candidates is recently an integral and demanding endeavor to the pharmaceutical industry. We should always keep searching for drugs that show marked advantages upon the formerly subsisting corresponding drugs such as betterment in bioactivity, lack of adverse side effects, reduced toxicity, enhanced stability and less production rate. The metaphors of nitrogen-based heterocycles possess a unique position being a pivotal resource of medicative agents in pharmaceutical chemistry and 75% of available drugs in the market are nitrogen-containing heterocyclic compounds. Among these heterocycles, triazoles are most consequential and ubiquitous heterocycles which are present in a variety of therapeutic agents like antimicrobial, anti-inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, antihypertensive, antimalarial, local anaesthetic, antianxiety, antidepressant, antihistaminic, antioxidant, antitubercular, anti Parkinson′s, antidiabetic, antiobesity and immunomodulatory etc. 1,2,3 and 1,2,4-triazole has been acknowledged as pharmacologically important scaffolds due to their potent activities. The present research is an effort to add the pharmacologically active 1,2,4- triazole derivatives in the current widespread library of these drugs. The present thesis copes with the preparation, spectral analysis and biological evaluation of N-ethyl-3,5-subsituted-1,2,4-triazoles and N-phenyl-3,5-subsituted-1,2,4- triazoles. The work began from the synthesis of ethyl 1-phenylcarbamoylpiperidine-4- carboxylate (2) which was synthesized by incessant mixing of ethyl isonipecotate and phenyl isocyanate in watch glass for 10-15 minutes. Hydrazine hydrate was added to Ethyl 1-phenylcarbamoyl-piperidine-4-carboxylate (2) and stirred for 4-5 hours, forming 1-(phenylcarbamoyl)-piperidine-4-carboxamide (3). Then 1-(phenylcarbamoyl)- piperidine-4-carboxamide (3) was taken in 100 ml RBF and ethyl isothiocyanate/ phenyl isothiocyanate were added with ethanol and refluxed and stirred for 4-5 hours which lead to the synthesis of 4-ethyl-(1-(1-phenylcarbamoyl)piperidine)thiosemicarbazide (4 & 5). 4 & 5 were cyclized to 4-ethyl-5-(1-(1-phenylcarbamoyl)piperidine)-4H-1,2,4-triazole-3- thiol and 4-phenyl-5-(1-(1-phenylcarbamoyl)piperidine)-4H-1,2,4-triazole-3-thiol (6 & 7) using 1% NaOH and refluxed for 4 hours then acidified by dilute hydrochloric acid. SUMMARY Page # 4 The last step was the linking of compounds 6 & 7 separately with the electrophiles 9a-o so as to get end products 10a-o & 11a-o. In this final step 6 & 7 were dissolved in ethanolic solution of KOH and stirred for 30 minutes and then precusors 9a-o were added distinctively and refluxed with sustained stirring for 4-5 hours. Reaction mixture was poured in distilled water and the precipitated products were obtained as 10a-o; 11a o. The structures of all the synthesized compounds were verified by the analysis of spectral data using infrared (IR), nuclear magnetic resonance (NMR both 1H-, 13C-NMR) spectroscopy and EI-MS and HR-EI-MS mass spectrometry. The synthetic protocol used for the synthesis is given below.......All the synthesized compounds were screened to check their anti-enzymatic potential against 15-lipoxygenase enzyme. The test was carried out according to the chemiluminescence method of Kondo and fellows with some changes. In vitro 15-LOX inhibition of compounds 10a-o and 11a-o was signaled by using quercetin (IC50 4.86 ± 0.14 µM) as reference. In case of compounds 10a-o, a variance in the enzyme inhibition SUMMARY Page # 6 was noticed and the inhibition values were ranging from 17.52 ± 0.67 to 108.73 ± 0.72 μM. The compounds 10b, 10c, 10e & 10g demonstrated promising inhibitory capability with IC50 values of 17.52 ± 0.67, 36.24 ± 0.83, 35.61 ± 0.81 and 36.52 ± 0.58 μM, respectively. The series of fifteen compounds 11a-o displayed excellent to moderate inhibitory potential (IC50 values ranges between 9.25 ± 0.26 to 56.35 ± 0.84 µM) against the probed enzyme. The compounds 11c and 11f were found to be the most influential 15-LOX inhibitors with IC50 values of 9.25 ± 0.26 and 9.54 ± 0.17 µM, respectively followed by 11d and 11g (IC50 13.64 ± 0.24 & 21.82 ± 0.35 µM). From the interpretation of the structure activity relationship (SAR), it is concluded that within the prepared derivatives, both the positions and type of substituents at the aryl group are performing phenomenal role in 15-LOX inhibitory activities. The synthesized analogs (10a-o & 11a o) were further assessed for their cytotoxicity by the MTT assay where the compound 10g was the most slightly toxiferous, exhibiting 89.5 ± 1.6% cell survival; meanwhile 10f was specified as the most noxious analogue with cell viability of 14.7 ± 1.2%. The increasing order of cell lethality was as: 10g < 10b < 10l < 10d. In second series, the compound 11c showed 83.5 ± 1.3% cell subsistence found least toxic, following this is 10d that displayed 78.4 ±1.2% cells existence. The most toxic compound 11m was passive against the enzyme 15-LOX. The increasing order in cell fatality was found as 11c < 11d < 11f < 11j < 11a < 11b < 11o. The ADME (absorption, distribution, metabolism, excretion) features of molecules mark them as an orally active drug in humans, are anticipated by Lipinski‟s rule of five and were calculated by MedChem Designer software ver 3.0. The compounds of both series (10a-o & 11a-o) all have TPSA values < 140 Å2, which again signify the really good bioavailability of the molecules. The chemistry of active sites and various functionalities liable for the best therapeutic potency of all the synthesized compounds was validated via docking studies. Demonstration of protein drug interaction helped us in knowing the various binding sites and binding constant to explain the stay of the drugs in the body, their circulation, metabolism, elimination and pharmacodynamics. Docking of the most active inhibitors from both series was carried off and all the docked compounds were observed to bind up the same domain as arachidonic acid and it disclosed the presence of several hydrogen bonded associations. In addition several hydrophobic associations like δ-π interaction, π alkyl interactions and anion-π interaction were also seen. SUMMARY Page # 7 The biological screening studies resulted in the identification of a list of compounds (10b, 10c, 10e, 10g, 11c, 11d, 11f, and 11g) with broad spectrum biological and pharmacological applications. These compounds may be recognized by the pharmacological world as new exclusive, lucrative and human friendly medicinal agents for the improvement of mankind
Gov't Doc #: 24077
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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