Electronic Theses and Dissertations


Amir E. Wahba

Date of Award


Document Type


Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Mark T. Hamann

Second Advisor

Takashi Tomioka

Third Advisor

Keith Hollis


Toxicity associated with bioactive natural products is considered as a major obstacle in the process of drug discovery. Manzamine A (MA) is one such candidate that requires optimization to overcome the toxicity problem. The manzamine alkaloids represents a unique class of natural products that have shown a diverse range of bioactivities including antimicrobial, antiparasitic, cytotoxicity, anti-inflammatory, pesticidial, and was shown to possess activity against HIV-1 and AIDS opportunistic infections. The greatest potential for the manzamine alkaloids appears to be against malaria and neuroinflammation. Experimental and modeling studies suggested that the planer ?-carboline moiety can act as DNA intercalator and hence induce toxicity. Thus either modification or the replacement of the ?-carboline moiety with other heterocycles could eliminate DNA intercalation and will be a huge step forward for generating manzamine-like analogs with similar or better biological activities and reduced toxicity. Using an optimized purification approach that utilized an acid-base treatment of the acetone extract of the Indonesian sponge Acanthostrongylophora sp., 100 g scale of pure manzamine A and 8-hydroxymanzamine A were obtained. Further purification of the more polar fractions led to the isolation of the known manzamines: manzamine F, 12,34-oxamanzamine E, 31-keto-12,34-oxa-32,33-dihydroircinal A, along with two new manzamine-related analogs, acantholactone with unprecedented ?-lactone and 2,21,28-trioxomanzamine J. Twenty manzamine A amides were synthesized through the nitration, reduction and acylation of C-6 and C-8 of the ?-carboline moiety. These analogs were evaluated for in vitro antimalarial and antimicrobial activities. The amides of MA showed significantly reduced cytotoxicity against Vero cells, although were less active than MA. Two amides 6-cyclohexyamidomanzamine A and 8-n-hexamidomanzamine A showed potent antimalarial activity in vitro against Plasmodium falciparum were further evaluated in vivo in Plasmodium berghei infected mice. Oral administration of these analogs at the dose of 30 mg/kg (once daily for three days) caused parasitemia suppression of 24% and 62%, respectively, with no apparent toxicity. Aminomanzmaines were observed to be unstable in solution and this instability affected the yield of the amides. This instability inspired the development of a simple and practical approach for the one-pot conversion of nitroarenes into amide derivatives. HOAc/Zn were utilized as a reducing agent and acyl chloride/Et3N were used as the acylating agent in DMF with good yield (?60%) of the amide. This method was applicable to 6-nitromanzamine A, where the yield of 6-cyclohexamidemanzamine A was significantly improved (56%) by this approach relative to starting with 6-aminomanzamine A (17%). N-Alkylation of the aminomanzamines was also problematic because of the instability issue. Utilizing the same reducing system (HOAc/Zn), a simple, mild, cost effective, and green approach for the reductive mono N-alkylation of nitroarenes was developed. Carbonyl compounds were utilized as the alkyl source in methanol. Excellent yields were obtained with stoichiometric control of mono over dialkylated products. In order to show the general applicability of our optimized conditions, five natural products: harmane, estradiol, quinine, manzamine F and curcudiol were nitrated and modified using our green N-alkylation strategy. Our new reductive alkylation conditions were well tolerated by the nitrated natural products and afforded moderate to excellent yields. The straightforward oxidation of ircinal A to ircinoic acid inspired utilizing the decarboxylative cross coupling (DCC) approach for the replacement of the ?-carboline moiety with other heterocycles. Optimization of the DCC reaction was completed using (S)-perrilic acid as a model compound; however, failed with ircinoic acid. We then switched to generate the ircinal derived triflate and Suzuki coupling approach. Our proposed scheme was based on the Birch reduction of ircinal A followed by an oxidative deformylation that should generate the corresponding oxo derivative that could be converted to the derived triflate. New and unexpected sequences of reactions were observed in the Birch reduction of ircinal A under atmospheric air. A sequential Birch reduction-elimination-oxidative deformylation were occurred and yielded the unexpected ircinal-derived enone. Further optimizations are needed to convert the new enone to the corresponding triflate.





To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.