Dihydropyrimidones: A ligands urease recognition study and mechanistic insight through in vitro and in silico approach
- PDF / 1,846,948 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 16 Downloads / 182 Views
Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02643-z
ORIGINAL RESEARCH
Dihydropyrimidones: A ligands urease recognition study and mechanistic insight through in vitro and in silico approach Farman Ali Khan1 Shahbaz Shamim2 Nisar Ullah3 Muhammad Arif Lodhi1 Khalid Mohammed Khan2,4 Kanwal2 Farman Ali2 Sahib Gul Afridi1 Shahnaz Perveen5 Ajmal Khan6 ●
●
●
●
●
●
●
●
●
1234567890();,:
1234567890();,:
Received: 5 July 2020 / Accepted: 23 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Scaffold varied dihydropyrimidone derivatives 1–20 were evaluated for their selective urease inhibitory kinetics potential. Compounds 1, 2, 3, 4, 5, 6, and 12 were found to be the most promising urease inhibitors and showed the inhibition (Ki values) within the range of 9.9 ± 0.5 to 18.3 ± 0.4 µM. Lineweaver–Burk plot, Dixon plot and their secondary replots confirm that all these molecules have followed competitive mode of inhibition. Docking arrangements (MOE) revealed that all the ligands bind in the active site and therefore compete with substrate urea. Molecular docking studies of all compounds have confirmed the binding interactions of various ligands with the amino acid residues as well as Ni atoms of active site. Furthermore, these compounds 1–20 were also tested for their cytotoxicity against human neutrophils and plants and were found to be non-toxic. Keywords Dihydropyrimidones Enzyme kinetics Michaelis–Menten kinetics Neutrophil based cytotoxicity Phytotoxicity ●
●
Introduction Urease (urea amidohydrolase, EC 3.5.1.5) belongs to the family of metalloenzyme that comprises of two nickel
* Muhammad Arif Lodhi [email protected] * Ajmal Khan [email protected] 1
Department of Biochemistry, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa 23200, Pakistan
2
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
3
Chemistry Department, King Fahd University of Petroleum & Minerals, Dhahran 31261, Saudi Arabia
4
Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
5
PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan
6
Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
●
●
atoms in its core structure. It catalyzes the hydrolysis of urease into NH3 and carbamate which spontaneously hydrolyzed further and generates another molecule of ammonia along with carbon dioxide [1–4]. The speed of this reaction is approximately 1014 times to that of uncatalyzed reaction. In soluble form, these two molecules of ammonia and a molecule of carbonic acid are in equilibrium with their protonated and deprotonated state which results in a net increase of pH to some extent [5]. Ureases are widely distributed in nature and can be found in var
Data Loading...
