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Drug-1,3,4-Thiadiaz...
Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase : Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation
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- Ujan, Rabail (author)
- Univ Sindh, Dr MA Kazi Inst Chem, Jamshoro 76080, Pakistan
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- Saeed, Aamer (author)
- Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan
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- Channar, Pervaiz Ali (author)
- Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan
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- Larik, Fayaz Ali (author)
- Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan
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- Abbas, Qamar (author)
- Univ Sindh, Dept Physiol, Jamshoro 76080, Pakistan
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- Alajmi, Mohamed F. (author)
- King Saud Univ, Dept Pharmacognosy, Coll Pharm, Riyadh 11451, Saudi Arabia
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- El-Seedi, Hesham (author)
- Uppsala universitet,Farmakognosi
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- Rind, Mahboob Ali (author)
- Univ Sindh, Dr MA Kazi Inst Chem, Jamshoro 76080, Pakistan
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- Hassan, Mubashir (author)
- Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea
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- Raza, Hussain (author)
- Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea
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- Seo, Sung-Yum (author)
- Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea
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(creator_code:org_t)
- 2019-02-28
- 2019
- English.
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In: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 24:5
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https://uu.diva-port... (primary) (Raw object)
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Abstract
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- A small library of new drug-1,3,4-thiazidazole hybrid compounds (3a-3i) was synthesized, characterized, and assessed for their acetyl cholinesterase enzyme (AChE) inhibitory and free radical scavenging activities. The newly synthesized derivatives showed promising activities against AChE, especially compound 3b (IC50 18.1 +/- 0.9 nM), which was the most promising molecule in the series, and was substantially more active than the reference drug (neostigmine methyl sulfate; IC50 2186.5 +/- 98.0 nM). Kinetic studies were performed to elucidate the mode of inhibition of the enzyme, and the compounds showed mixed-type mechanisms for inhibiting AChE. The Ki of 3b (0.0031 mu M) indicates that it can be very effective, even at low concentrations. Compounds 3a-3i all complied with Lipinski's Rule of Five, and showed high drug-likeness scores. The pharmacokinetic parameters revealed notable lead-like properties with insignificant liver and skin-penetrating effects. The structure-activity relationship (SAR) analysis indicated pi-pi interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- mixed-type AChE inhibitors
- ADMET parameters
- pharmacokinetics
- drug-likeness
- synthesis
- antioxidant activity
- molecular docking
- 1
- 3
- 4-thiadiazole-drug
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- ref (subject category)
- art (subject category)
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Ujan, Rabail
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Saeed, Aamer
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Channar, Pervaiz ...
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Larik, Fayaz Ali
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Abbas, Qamar
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Alajmi, Mohamed ...
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show more...
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El-Seedi, Hesham
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Rind, Mahboob Al ...
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Hassan, Mubashir
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Raza, Hussain
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Seo, Sung-Yum
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MEDICAL AND HEAL ...
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Uppsala University