Therapeutic potential of 1,3,4-oxadiazoles as potential lead compounds for the treatment of Alzheimer's disease

Naseem, Saira; Temirak, Ahmed; Imran, Aqeel; Jalil, Saquib; Fatima, Shamool; Taslimi, Parham; Iqbal, Jamshed; Tasleem, Mussarat; Tahir, M.N.; Shafiq, Zahid

doi:10.1039/d3ra01953e

Cited by 5 publications

(2 citation statements)

References 31 publications

(49 reference statements)

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“…were observed with amino acid residues such as GLY67, TYR407, TYR69, PHE352, and ILE180. [34] the SwissADME platform incorporated the boiled egg plot, a rapid, straightforward, method for forecasting the passive gastrointestinal absorption of a chemical. [35,36] The visual representation of gastrointestinal absorption, known as the egg-shaped plot, depicts the white portion of the egg to symbolize this process.…”

Section: Enzyme Kinetic Studiesmentioning

confidence: 99%

2‐Oxoquinoline‐based‐thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors

Basri,

Fatima,

Jalil

et al. 2023

Archiv der Pharmazie

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Alzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long‐term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2‐oxoquinoline‐based thiosemicarbazones 9a–r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO‐A and MAO‐B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO‐A, MAO‐B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 μM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.

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Section: Enzyme Kinetic Studiesmentioning

confidence: 99%

2‐Oxoquinoline‐based‐thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors

Basri,

Fatima,

Jalil

et al. 2023

Archiv der Pharmazie

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“…This feature is relevant to a variety of disorders 48 associated with oxidative damage. Oxadiazole derivatives have been studied for their capacity to shield brain cells from injury, perhaps making them effective in the treatment of neurodegenerative illnesses such as Alzheimer's and Parkinson's [13,14]. Some derivatives 51 have demonstrated cardiovascular effects, such as vasodilation (blood vessel widening) and possible utility in the treatment of cardiovascular problems.…”

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confidence: 99%

Study of Oxadiazole derivatives as precursor for multi-functional inhibitor to SARS-CoV-2: A detailed virtual screening analysis

Kumar,

Kumar

2024

Mong. J. Chem.

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SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is highly contagious and has caused widespread loss of life. In the quest to find effective antiviral agents, attention has turned to oxadiazole derivatives, which are known for their potential antiviral properties in such as CoViTris2020, ChloViD2020, etc. To evaluate their effectiveness, molecular docking and molecular dynamics simulations are conducted for various oxadiazole derivative in interactions with critical proteins involved in the viral infection process. These proteins encompass transmembrane-serine-2 (TMPRSS2), 3-chymotrypsin-like-protease (3CLpro), angiotensin-converting-enzyme-2 (ACE2), and papain-like-protease (PLpro). The study shows that the oxadiazole derivatives exhibited their most stable complexes when interacting with TMPRSS2 in comparison to 3CLpro, ACE2, and PLpro. In particular, Oxa8 displayed a binding energy of -6.52 kcal/mol with TMPRSS2. In contrast, the binding energies with ACE2, 3CLpro, and PLpro were -5.74, -4.56, and -5.56 kcal/mol, respectively. RMSD analysis during MD simulations demonstrated that the complex structure remained consistently stable. During the initial 2 ns, the RMSD value for the ligand concerning its interaction with the protein backbone hovered around 2 Å, indicating a sustained level of structural stability. In conclusion, this study suggests that oxadiazole derivative Oxa8 holds promise as a potential inhibitor of SARS-CoV-2, particularly due to its strong binding affinity with TMPRSS2 and its enduring structural stability observed in molecular dynamics simulations.

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Benzohydrazide as a good precursor for the synthesis of novel bioactive and anti-oxidant 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives: Structural determination, biological and anti-oxidant activity

Briki,

Lahreche,

Abbassi

et al. 2024

Arabian Journal of Chemistry

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Therapeutic potential of 1,3,4-oxadiazoles as potential lead compounds for the treatment of Alzheimer's disease

Abstract: Monoamine oxidase and cholinesterase enzymes are important targets for the treatment of several neurological diseases especially depression, Parkinson disease and Alzheimer's.

Cited by 5 publications

References 31 publications

2‐Oxoquinoline‐based‐thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors

2‐Oxoquinoline‐based‐thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors

Study of Oxadiazole derivatives as precursor for multi-functional inhibitor to SARS-CoV-2: A detailed virtual screening analysis

Benzohydrazide as a good precursor for the synthesis of novel bioactive and anti-oxidant 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives: Structural determination, biological and anti-oxidant activity

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