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Structure-activity relationship studies in chemoreception, toxicology and medicinal chemistry

Ptchelintsev, Dmitri Stanislav
http://rave.ohiolink.edu/etdc/view?acc_num=case1060866168

Abstract Details

1993, Doctor of Philosophy, Case Western Reserve University, Chemistry.
The structure of chemicals determines their activity in biological systems. In this work, the Computer-Automated Structure Evaluation (CASE) methodology was used to study causal relationships between structural and physicochemical parameters of organic chemicals and their biological effects. In the area of chemoreception, correlations were established between the molecular parameters and musky odor of 87 nitro-free aromatic musks and 65 of their odorless structural analogs. Lipophilicity and several substructural descriptors were found to be important for musky odor. The structure-odor model was used to predict a priori the strength of musky odor for 20 new chemicals. Structural requirements for musky odor indicate that a hypothetical musky olfactory receptor must have a hydrophilic H-bond donor site and a narrow hydrophobic domain. In toxicology, relationships were studied between the structure of chemicals used in cosmetic and personal care products and their potential to cause eye irritation. The following functionalities were found to contribute to eye irritation: carboxylate and sulfonate groups in anionic surfactants, phenolic moieties in non-ionic surfactants, amino groups, halogenated and unsaturated structures , anhydrides and epoxides. A priori predictions of the eye irritation potential were made for 21 chemicals, chemical mixtures such as coconut oil, eucalyptus oil, etc., and some polymers. In the medicinal area, three groups of antifungal agents were studied: antibiotics, allylamine derivatives, and triazole alcohols. For triazole alcohols, structure-antifungal activity relationships were studied in conjunction with the structure-teratogenicity and structure-therapeutic index relationships. The cyano, methoxy groups, and ortho-difluorination on the aromatic rings decreases antifungal activity, but not the therapeutic index because of the concomitant negative contribution to teratogenicity. Metabolically deactivating para-substitution in the benzene rings is beneficial for the therapeutic index in agreement with the idea of metabolically induced teratogenicity. Structure-activity model was used to predict the teratogenicity and antifungal activity of SCH 39304 and ICI 156,066 and to optimize the structure and therapeutic index of the latter. Based on the structure-activity model of antifungal allylamines, superior fungicidal activity against Candida albicans and Cryptococcus neoformans coupled with negligible hemolytic activity was discovered for p-dimethylaminostyryl β-naphthiazole
Gilles Klopman (Advisor)
160 p.
Chemistry, General
Structure-activity relationships; Chemoreception, toxicology and medicinal chemistry

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Citations

  • Ptchelintsev, D. S. (1993). Structure-activity relationship studies in chemoreception, toxicology and medicinal chemistry [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1060866168

    APA Style (7th edition)

  • Ptchelintsev, Dmitri. Structure-activity relationship studies in chemoreception, toxicology and medicinal chemistry. 1993. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1060866168.

    MLA Style (8th edition)

  • Ptchelintsev, Dmitri. "Structure-activity relationship studies in chemoreception, toxicology and medicinal chemistry." Doctoral dissertation, Case Western Reserve University, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1060866168

    Chicago Manual of Style (17th edition)

case1060866168
706
© 1993, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.