Mandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations

Muhammed Trawally; Kübra Demir-Yazıcı; Serap İpek Dingiş-Birgül; Kerem Kaya; Atilla Akdemir; Özlen Güzel-Akdemir

doi:10.1016/j.bioorg.2022.105688

Mandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations

Muhammed Trawally, Kübra Demir-Yazıcı, Serap İpek Dingiş-Birgül, Kerem Kaya, Atilla Akdemir, Özlen Güzel-Akdemir^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

A series of new spirothiazolidinone derivatives with a mandelic acid moiety were synthesized and subsequently tested in growth inhibition assays against Mycobacterium tuberculosis strain H37Rv. Compound 16 displayed the highest inhibition value of 98% at lower than 6.25 µg/mL concentration. A single crystal X-ray analysis was conducted on this compound to confirm the structure and determine its absolute configuration. Afterwards, reverse docking and molecular dynamics simulations of this specific stereoisomer were performed against a selection of 10 putative targets of M. tuberculosis to suggest possible mechanisms of action. Our results suggest HadAB, Pks13, DprE1, FadD32 and InhA as possible target proteins for the observed antimycobacterial activity of compound 16.

Original language	English
Article number	105688
Journal	Bioorganic Chemistry
Volume	121
DOIs	https://doi.org/10.1016/j.bioorg.2022.105688
Publication status	Published - Apr 2022

Bibliographical note

Publisher Copyright:
© 2022

Keywords

4-Thiazolidinone
Enoyl-[acyl-carrier-protein]-reductase
Mandelic acid
Molecular docking
Molecular dynamics
MtInhA
Mycobacterium tuberculosis
Spirothiazolidinone

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bioorg.2022.105688

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title = "Mandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations",

abstract = "A series of new spirothiazolidinone derivatives with a mandelic acid moiety were synthesized and subsequently tested in growth inhibition assays against Mycobacterium tuberculosis strain H37Rv. Compound 16 displayed the highest inhibition value of 98% at lower than 6.25 µg/mL concentration. A single crystal X-ray analysis was conducted on this compound to confirm the structure and determine its absolute configuration. Afterwards, reverse docking and molecular dynamics simulations of this specific stereoisomer were performed against a selection of 10 putative targets of M. tuberculosis to suggest possible mechanisms of action. Our results suggest HadAB, Pks13, DprE1, FadD32 and InhA as possible target proteins for the observed antimycobacterial activity of compound 16.",

keywords = "4-Thiazolidinone, Enoyl-[acyl-carrier-protein]-reductase, Mandelic acid, Molecular docking, Molecular dynamics, MtInhA, Mycobacterium tuberculosis, Spirothiazolidinone",

author = "Muhammed Trawally and K{\"u}bra Demir-Yazıcı and Dingi{\c s}-Birg{\"u}l, {Serap İpek} and Kerem Kaya and Atilla Akdemir and {\"O}zlen G{\"u}zel-Akdemir",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2022",

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doi = "10.1016/j.bioorg.2022.105688",

language = "English",

volume = "121",

journal = "Bioorganic Chemistry",

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T1 - Mandelic acid-based spirothiazolidinones targeting M. tuberculosis

T2 - Synthesis, in vitro and in silico investigations

AU - Trawally, Muhammed

AU - Demir-Yazıcı, Kübra

AU - Dingiş-Birgül, Serap İpek

AU - Kaya, Kerem

AU - Akdemir, Atilla

AU - Güzel-Akdemir, Özlen

PY - 2022/4

Y1 - 2022/4

N2 - A series of new spirothiazolidinone derivatives with a mandelic acid moiety were synthesized and subsequently tested in growth inhibition assays against Mycobacterium tuberculosis strain H37Rv. Compound 16 displayed the highest inhibition value of 98% at lower than 6.25 µg/mL concentration. A single crystal X-ray analysis was conducted on this compound to confirm the structure and determine its absolute configuration. Afterwards, reverse docking and molecular dynamics simulations of this specific stereoisomer were performed against a selection of 10 putative targets of M. tuberculosis to suggest possible mechanisms of action. Our results suggest HadAB, Pks13, DprE1, FadD32 and InhA as possible target proteins for the observed antimycobacterial activity of compound 16.

AB - A series of new spirothiazolidinone derivatives with a mandelic acid moiety were synthesized and subsequently tested in growth inhibition assays against Mycobacterium tuberculosis strain H37Rv. Compound 16 displayed the highest inhibition value of 98% at lower than 6.25 µg/mL concentration. A single crystal X-ray analysis was conducted on this compound to confirm the structure and determine its absolute configuration. Afterwards, reverse docking and molecular dynamics simulations of this specific stereoisomer were performed against a selection of 10 putative targets of M. tuberculosis to suggest possible mechanisms of action. Our results suggest HadAB, Pks13, DprE1, FadD32 and InhA as possible target proteins for the observed antimycobacterial activity of compound 16.

KW - 4-Thiazolidinone

KW - Enoyl-[acyl-carrier-protein]-reductase

KW - Mandelic acid

KW - Molecular docking

KW - Molecular dynamics

KW - MtInhA

KW - Mycobacterium tuberculosis

KW - Spirothiazolidinone

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U2 - 10.1016/j.bioorg.2022.105688

DO - 10.1016/j.bioorg.2022.105688

M3 - Article

C2 - 35189443

AN - SCOPUS:85124723907

SN - 0045-2068

VL - 121

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

M1 - 105688

ER -

Mandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations

Abstract

Bibliographical note

Keywords

UN SDGs

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