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Structure-activity relationship of pyridinium oximes as therapeutics for organophosphorus nerve agent poisoning

Gambino, Adriana (2021) Structure-activity relationship of pyridinium oximes as therapeutics for organophosphorus nerve agent poisoning. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase and pose a threat to both military personnel and civilians. Despite providing limited protection, 2-pralidoxime (2-PAM) is the only United States Food and Drug Administration approved therapeutic for OPNA poisoning. Unfortunately, the spectrum of 2-PAM for a panel of OPNAs is narrow, necessitating further research. Herein, the design, synthesis, and in vitro activity of 2-PAM analogs is presented. Initial efforts used a methyl scan approach to identify ring positions of 2-PAM that could tolerate modification. Subsequently, structure-activity relationship (SAR)-guided molecular docking was used to rationalize feasible binding modes for 2-PAM and the reported methyl scan derivatives. Overall, the data in Section 2.1 provided new insights, e.g., that the 4-position of 2-PAM is tolerant of modifications. This information has proven to be useful in the rational design of new analogs.
In Section 2.2, a synthetic strategy for 4-alkyl and aryl ether and 4-alkyl and aryl sulfide analogs was developed. With these analogs and paraoxon as an OPNA mimic, SAR studies were performed. Through this study, 4-thiophenyl-2-PAM and 4-phenoxy-2-PAM were identified as efficient reactivators of inhibited acetylcholinesterase. Furthermore, the SAR study in Section 2.3 revealed that aryl sulfides were generally more tolerant of additional substituents in comparison to related ether analogs.
The final section of work (Section 2.4) details the design, synthesis, and in vitro evaluation of phenalkyl, phenalkyl ether, and phenethyl phenyl ether analogs. In vitro testing of these analogs revealed that 4-phenethyl-2-PAM was a superior reactivator of acetylcholinesterase inhibited by sarin, cyclosarin, VX, and tabun in comparison to 2-PAM.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Gambino, Adrianaadg89@pitt.eduadg890000-0003-0825-5879
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKoide,
Committee MemberWipf,
Committee MemberHorne,
Committee MemberLeikauf,
Date: 3 May 2021
Date Type: Publication
Defense Date: 18 February 2021
Approval Date: 3 May 2021
Submission Date: 25 March 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 731
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Organophosphorus nerve agents; structure-activity relationship; medicinal chemistry
Date Deposited: 03 May 2021 14:41
Last Modified: 03 May 2023 05:15


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