PMID- 37649576
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230901
IS  - 2046-2069 (Electronic)
IS  - 2046-2069 (Linking)
VI  - 13
IP  - 36
DP  - 2023 Aug 21
TI  - Theophylline-based hybrids as acetylcholinesterase inhibitors endowed with 
      anti-inflammatory activity: synthesis, bioevaluation, in silico and preliminary 
      kinetic studies.
PG  - 25616-25634
LID - 10.1039/d3ra04867e [doi]
AB  - In this study, we investigated the conjugation of theophylline with different 
      compounds of natural origin hoping to construct new hybrids with dual activity 
      against cholinergic and inflammatory pathways as potential agents for the 
      treatment of Alzheimer's disease (AD). Out of 28 tested hybrids, two hybrids, 
      acefylline-eugenol 6d and acefylline-isatin 19, were able to inhibit 
      acetylcholinesterase (AChE) at low micromolar concentration displaying IC(50) 
      values of 1.8 and 3.3 muM, respectively, when compared to the galantamine standard 
      AChE inhibitor. Moreover, the prepared hybrids exhibited a significant 
      anti-inflammatory effect against lipopolysaccharide induced inflammation in RAW 
      264.7 and reduced nitric oxide (NO), tumor necrosis alpha (TNF-alpha), interleukin-1beta 
      (IL-1beta), and interleukin-6 (IL-6) levels in a dose dependent manner. These 
      hybrids demonstrated significant reductions in nitric oxide (NO), tumor necrosis 
      alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) levels in RAW 
      264.7 cells induced by lipopolysaccharide (LPS). The findings of this study were 
      further explained in light of network pharmacology analysis which suggested that 
      AChE and nitric oxide synthase were the main targets of the most active 
      compounds. Molecular docking studies revealed their ability to bind to the heme 
      binding site of nitric oxide synthase 3 (NOS-3) and effectively occupy the active 
      site of AChE, interacting with both the peripheral aromatic subsite and catalytic 
      triad. Finally, the compounds demonstrated stability in simulated gastric and 
      intestinal environments, suggesting potential absorption into the bloodstream 
      without significant hydrolysis. These findings highlight the possible therapeutic 
      potential of acefylline-eugenol 6d and acefylline-isatin 19 hybrids in targeting 
      multiple pathological mechanisms involved in AD, offering promising avenues for 
      further development as potential treatments for this devastating disease.
CI  - This journal is (c) The Royal Society of Chemistry.
FAU - Elgazar, Abdullah A
AU  - Elgazar AA
AUID- ORCID: 0000-0002-5851-3306
AD  - Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University P.O. 
      Box 33516 Kafrelsheikh Egypt.
FAU - El-Domany, Ramadan A
AU  - El-Domany RA
AD  - Department of Microbiology and Immunology, Faculty of Pharmacy, Kafrelsheikh 
      University P.O. Box 33516 Kafrelsheikh Egypt.
FAU - Eldehna, Wagdy M
AU  - Eldehna WM
AUID- ORCID: 0000-0001-6996-4017
AD  - Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh 
      University P.O. Box 33516 Kafrelsheikh Egypt.
FAU - Badria, Farid A
AU  - Badria FA
AD  - Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University Mansoura 
      Egypt faridbadria@gmail.com +20-1001762927.
LA  - eng
PT  - Journal Article
DEP - 20230829
PL  - England
TA  - RSC Adv
JT  - RSC advances
JID - 101581657
PMC - PMC10463010
COIS- The authors declare that there is no conflict of interest, and no funding was 
      associated with this manuscript.
EDAT- 2023/08/31 06:42
MHDA- 2023/08/31 06:43
PMCR- 2023/08/29
CRDT- 2023/08/31 03:59
PHST- 2023/07/19 00:00 [received]
PHST- 2023/08/20 00:00 [accepted]
PHST- 2023/08/31 06:43 [medline]
PHST- 2023/08/31 06:42 [pubmed]
PHST- 2023/08/31 03:59 [entrez]
PHST- 2023/08/29 00:00 [pmc-release]
AID - d3ra04867e [pii]
AID - 10.1039/d3ra04867e [doi]
PST - epublish
SO  - RSC Adv. 2023 Aug 29;13(36):25616-25634. doi: 10.1039/d3ra04867e. eCollection 
      2023 Aug 21.