Design, synthesis, biological and computational screening of novel pyridine-based thiadiazole derivatives as prospective anti-inflammatory agents.

Autor:	Podila N; Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Science, Technology & Research, Vadlamudi, Guntur, 522213, Andhra Pradesh, India., Penddinti NK; Vikas College of Pharmaceutical Sciences, Suryapet, Telangana, India., Rudrapal M; Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Science, Technology & Research, Vadlamudi, Guntur, 522213, Andhra Pradesh, India., Rakshit G; Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, India, Ranchi, 835215, Jharkhand, India., Konidala SK; Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Science, Technology & Research, Vadlamudi, Guntur, 522213, Andhra Pradesh, India., Pulusu VS; Ohio University, Department of Chemistry & Biochemistry, Athens, OH, USA, 45701., Bhandare RR; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, P O Box 346, Ajman, United Arab Emirates.; Centre of Medical and Bio-allied Health Sciences Research, Ajman University, P O Box 346, Ajman, United Arab Emirates., Shaik AB; St. Mary's College of Pharmacy, St. Mary's Group of Institutions Guntur, Affiliated to Jawaharlal Nehru Technological University Kakinada, Chebrolu, Guntur, 522212, Andhra Pradesh, India.; Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India.
Jazyk:	angličtina
Zdroj:	Heliyon [Heliyon] 2024 Apr 09; Vol. 10 (8), pp. e29390. Date of Electronic Publication: 2024 Apr 09 (Print Publication: 2024).
DOI:	10.1016/j.heliyon.2024.e29390
Abstrakt:	In this study, a novel series of pyridine-based thiadiazole derivatives ( NTD1-NTD5 ) were synthesized as prospective anti-inflammatory agents by combining substituted carboxylic acid derivatives of 5-substituted-2-amino-1,3,4-thiadiazole with nicotinoyl isothiocyanate in the presence of acetone. The newly synthesized compounds were characterized by FTIR, 1 H NMR, 13 C NMR, and mass spectrometry. First, the compounds underwent rigorous in vivo testing for acute toxicity and anti-inflammatory activity and the results revealed that three compounds- NTD1 , NTD2 , and NTD3 , displayed no acute toxicity and significant anti-inflammatory activity, surpassing the efficacy of the standard drug, diclofenac. Notably, NTD3 , which featured benzoic acid substitution, emerged as the most potent anti-inflammatory agent among the screened compounds. To further validate these findings, an in silico docking study was carried out against COX-2 bound to diclofenac (PDB ID: 1pxx). The computational analysis demonstrated that NTD2 , and NTD3 , exhibited substantial binding affinity, with the lowest binding energies (-8.5 and -8.4, kcal/mol) compared to diclofenac (-8.4 kcal/mol). This alignment between in vivo and in silico data supported the robust anti-inflammatory potential of these derivatives. Moreover, molecular dynamics simulations were conducted, extending over 100 ns, to examine the dynamic interactions between the ligands and the target protein. The results solidified NTD3 's position as a leading candidate, showing potent inhibitory activity through strong and sustained interactions, including stable hydrogen bond formations. This was further confirmed by RMSD values of 2-2.5 Å and 2-3Ǻ, reinforcing NTD3 's potential as a useful anti-inflammatory agent. The drug likeness analysis of NTD3 through SwissADME indicated that most of the predicted parameters including Lipinski rule were within acceptable limits. While these findings are promising, further research is necessary to elucidate the precise relationships between the chemical structures and their activity, as well as to understand the mechanisms underlying their pharmacological effects. This study lays the foundation for the development of novel anti-inflammatory therapeutics, potentially offering improved efficacy and safety profiles. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2024 The Authors.)
Databáze:	MEDLINE
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