دورية أكاديمية
أعرض في EDS

Identification of potent indolizine derivatives against Mycobacterial tuberculosis: In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies.

التفاصيل البيبلوغرافية
العنوان: Identification of potent indolizine derivatives against Mycobacterial tuberculosis: In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies.
المؤلفون: Venugopala KN; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban 4000, South Africa. Electronic address: kvenugopala@kfu.edu.sa., Chandrashekharappa S; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER-R), Raebareli, Lucknow, UP 226002, India. Electronic address: c.sandeep@niperraebareli.edu.in., Deb PK; Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology (BIT), Mesra, Ranchi 835215, Jharkhand, India. Electronic address: prankishoredeb@bitmesra.ac.in., Al-Shar'i NA; Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan; Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University, P.O. Box: 2713, Doha, Qatar., Pillay M; Department of Microbiology, National Health Laboratory Services, KZN Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa., Tiwari P; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER-R), Raebareli, Lucknow, UP 226002, India., Chopra D; Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal By-pass Road, Bhauri, Bhopal 462066, Madhya Pradesh, India., Borah P; Department of Biological Sciences and Bioengineering, Indian Institute of Technology (IIT), Kanpur, 208016, Uttar Pradesh, India., Tamhaev R; Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (LSPCMIB), UMR 5068, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France., Mourey L; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France., Lherbet C; Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (LSPCMIB), UMR 5068, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France., Aldhubiab BE; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia., Tratrat C; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia., Attimarad M; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia., Nair AB; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia., Sreeharsha N; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; Department of Pharmaceutics, Vidya Siri College of Pharmacy, Off Sarjapura Road, Bangalore 560035, India., Mailavaram RP; Department of Pharmaceutical Chemistry, Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Samtanagar, Dhule 424 001, Maharashtra, India., Venugopala R; Department of Public Health Medicine, Howard College Campus, University of KwaZulu-Natal, Durban 4001, South Africa., Mohanlall V; Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban 4000, South Africa., Morsy MA; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt.
المصدر: International journal of biological macromolecules [Int J Biol Macromol] 2024 Aug; Vol. 274 (Pt 2), pp. 133285. Date of Electronic Publication: 2024 Jun 24.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7909578 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0003 (Electronic) Linking ISSN: 01418130 NLM ISO Abbreviation: Int J Biol Macromol Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier
Original Publication: Guildford, Eng., IPC Science and Technology Press.
مواضيع طبية MeSH: Mycobacterium tuberculosis*/drug effects , Mycobacterium tuberculosis*/enzymology , Antitubercular Agents*/pharmacology , Antitubercular Agents*/chemistry , Molecular Docking Simulation* , Indolizines*/chemistry , Indolizines*/pharmacology , Microbial Sensitivity Tests*, Molecular Dynamics Simulation ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/metabolism ; Bacterial Proteins/chemistry ; Oxidoreductases/antagonists & inhibitors ; Oxidoreductases/metabolism ; Structure-Activity Relationship
مستخلص: In the current study, two sets of compounds: (E)-1-(2-(4-substitutedphenyl)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium derivatives (3a-3e); and (E)-3-(substitutedbenzoyl)-7-((hydroxyimino)methyl)-2-substitutedindolizine-1-carboxylate derivatives (5a-5j), were synthesized and biologically evaluated against two strains of Mycobacterial tuberculosis (ATCC 25177) and multi-drug resistant (MDR) strains. Further, they were also tested in vitro against the mycobacterial InhA enzyme. The in vitro results showed excellent inhibitory activities against both MTB strains and compounds 5a-5j were found to be more potent, and their MIC values ranged from 5 to 16 μg/mL and 16-64 μg/mL against the M. tuberculosis (ATCC 25177) and MDR-TB strains, respectively. Compound 5h with phenyl and 4-fluorobenzoyl groups attached to the 2- and 3-position of the indolizine core was found to be the most active against both strains with MIC values of 5 μg/mL and 16 μg/mL, respectively. On the other hand, the two sets of compounds showed weak to moderate inhibition of InhA enzyme activity that ranged from 5 to 17 % and 10-52 %, respectively, with compound 5f containing 4-fluoro benzoyl group attached to the 3-position of the indolizine core being the most active (52 % inhibition of InhA). Unfortunately, there was no clear correlation between the InhA inhibitory activity and MIC values of the tested compounds, indicating the probability that they might have different modes of action other than InhA inhibition. Therefore, a computational investigation was conducted by employing molecular docking to identify their putative drug target(s) and, consequently, understand their mechanism of action. A panel of 20 essential mycobacterial enzymes was investigated, of which β-ketoacyl acyl carrier protein synthase I (KasA) and pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (BioA) enzymes were revealed as putative targets for compounds 3a-3e and 5a-5j, respectively. Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.
Competing Interests: Declaration of competing interest Authors declare that they have no competing interest.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: 2-Substituted indolizine; MTB target validation; Molecular docking; Multidrug-resistant Mycobacterial tuberculosis; Mycobacterial tuberculosis
المشرفين على المادة: 0 (Antitubercular Agents)
0 (Indolizines)
0 (Bacterial Proteins)
EC 1.3.1.9 (InhA protein, Mycobacterium)
EC 1.- (Oxidoreductases)
274-40-8 (indolizine)
تواريخ الأحداث: Date Created: 20240626 Date Completed: 20240730 Latest Revision: 20240730
رمز التحديث: 20240730
DOI: 10.1016/j.ijbiomac.2024.133285
PMID: 38925196
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-0003
DOI:10.1016/j.ijbiomac.2024.133285