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THE DESIGN AND SYNTHESIS OF CYANINES AND ARYLIMIDAMIDE AZOLE HYBRIDS AS ANTILESIHMANAIAL AGENTS

Abdelhameed, Ahmed M
http://rave.ohiolink.edu/etdc/view?acc_num=osu1525738213459762

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Pharmacy.
Leishmaniasis is a neglected tropical disease; the number of fatalities it causes ranks it second to malaria among parasitic infections. The Leishmania parasite can cause cutaneous and visceral manifestations. Cutaneous leishmaniasis can lead to lifelong scars, and some forms can develop into mucocutaneous leishmaniasis. Visceral leishmaniasis, in which the liver, spleen, and bone marrow become infected, is fatal if left untreated. Currently, antimonial drugs remain a first line antileishmanial treatment in many areas and suffer from serious toxicity issues as well as resistance on the Indian subcontinent. Paromomycin is inexpensive, yet it is given to treat visceral leishmaniasis only by the parenteral route. Amphotericin B deoxycholate, another injectable antileishmanial drug, is nephrotoxic. Liposomal amphotericin B mitigates toxicity issues observed with the deoxycholate formulation, yet it is very expensive. Finally, miltefosine has the advantage of being orally bioavailable, but this antileishmanial drug is teratogenic. This dissertation describes research conducted on two classes of compounds with promising antileishmanial activity. The first class was inspired by the cyanine compound thiazole orange, a lead that was originally discovered through high throughput screening of almost 200,000 compounds. The second class of compounds possesses the arylimidamide scaffold. Lead arylimidamide DB766 displayed very potent antileishmanial activity with an IC50 value of 36 nM in L. donovani intracellular macrophage assay. Oral administration of DB766 led only to 71% reduction in liver parasitemia in L. donovani infected mice. The potent in vitro antileishmanial activity and encouraging in vivo efficacy of these two compounds partially inspired the synthesis of the two classes of molecules described in this dissertation in the hopes of identifying improved leads. Chapter 1 provides background information about leishmaniasis and reviews the current antileishmanial agents as well as candidate compounds in research and in preclinical trials. Finally, a brief background about the antileishmanial activity of previous cyanines and arylimidamides is presented. Chapter 2 provides the methodology on which the synthesis of cyanine analogs was based followed by the synthetic schemes for the cyanines investigated here. The in vitro antileishmanial assays will be discussed. Finally, DNA melting studies were carried out on selected cyanine analogs Chapter 3 will focus on arylimidamide azole hybrids. Firstly, the approach for the design of the analogs will be discussed followed by the synthetic schemes for both phenoxyalkyl and biphenoxyalkyl analogs. The in vitro antileishmanial activity, cytotoxicity, and in vivo efficacy of these analogs will also be presented. Regarding the phenoxyalkyl analogs. Most of the biphenoxy alkyl analogs displayed potency in the submicromolar range. In vivo evaluation of 3.27c was also determined in L. donovani-infected mice. Finally, a brief discussion concerning the metabolic stability of selected compounds will be given. Chapters 4 and 5 will provide the detailed chemical characterizations of cyanines and arylimidamide azole hybrids, while the NMR spectra of the target compounds appear in the appendix.
Karl Werbovetz (Advisor)
Organic Chemistry; Pharmaceuticals; Pharmacy Sciences

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Citations

  • Abdelhameed, A. M. (2018). THE DESIGN AND SYNTHESIS OF CYANINES AND ARYLIMIDAMIDE AZOLE HYBRIDS AS ANTILESIHMANAIAL AGENTS [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1525738213459762

    APA Style (7th edition)

  • Abdelhameed, Ahmed. THE DESIGN AND SYNTHESIS OF CYANINES AND ARYLIMIDAMIDE AZOLE HYBRIDS AS ANTILESIHMANAIAL AGENTS. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1525738213459762.

    MLA Style (8th edition)

  • Abdelhameed, Ahmed. "THE DESIGN AND SYNTHESIS OF CYANINES AND ARYLIMIDAMIDE AZOLE HYBRIDS AS ANTILESIHMANAIAL AGENTS." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1525738213459762

    Chicago Manual of Style (17th edition)

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