Optimization of Enantiopure tetrahydro-β-carbolines as Potent Antimalarials and Exploration of salicylic acid analogs for combating multidrug-resistant Neisseria gonorrhoeae

dc.contributor.authorAlMolhim, Hanan Sulimanen
dc.contributor.committeechairCarlier, Paul R.en
dc.contributor.committeememberEtzkorn, Felicia A.en
dc.contributor.committeememberLowell, Andrew Nesemannen
dc.contributor.committeememberSantos, Websteren
dc.contributor.departmentChemistryen
dc.date.accessioned2023-05-16T08:00:58Zen
dc.date.available2023-05-16T08:00:58Zen
dc.date.issued2023-05-15en
dc.description.abstractThe emergence of drug resistance towards existing drugs is a constant challenge in the fight against many diseases including Malaria and gonorrhoeae. To evade resistance, new targets must be engaged, and to do that, new structural classes of anti-infective must be prepared and evaluated. During the course of my PhD journey, I had the opportunity to investigate and optimize the antimalarial candidate (±)-2-3b, and salicylic acid (4-1a) as an anti-gonorrhea treatment. Malaria is a life-threatening mosquito-borne disease. In 2021, there were 247 million cases of malaria and the estimated number of malaria deaths stood at 619,000. Because of the rapid development of resistance to all current antimalarials, discovery of antimalarials with unexploited mechanisms of action is critical to reduce malaria mortality. In the Carlier group, our initial approach focused on discovery of inhibitors of the methylerythritol phosphate (MEP) pathway for isoprenoid precursor biosynthesis, since this pathway is essential for Plasmodium falciparum and absent in human. Application of the isopentenyl pyrophosphate (IPP) chemical rescue screen to the compounds of the Malaria Box, a collection of 400 antimalaria candidates with unknown mechanisms of action, identified tetrahydro-β-carboline 2-1 (MMV008138) as an inhibitor of the MEP pathway. Chapter 2 of this work discusses similarity searching of the Novartis portion of the hit set (5K compounds), from the original 20K compound hit set of the Malaria Box, and identifying tetrahydro-β-carboline GNF-Pf-5009, designated as (±)-2-3b. Preparation of pure enantiomers, by resolution, demonstrated the pharmacological superiority of (R)-2-3b over (S)-2-3b, which was found to have good asexual blood stage (ABS) inhibition potency against malarial parasites P. falciparum, and low general cytotoxicity. However, (R)-2-3b was found not orally efficacious in a P. berghei mouse model of malaria. We concluded that the lack of oral efficacy of (R)-2-3b was due to its poor drug-like qualities, in particular its high molecular weight and low solubility. Chapter 3 of this work explores modifications of (R)-2-3b ((R)-3-5Aa) that were expected to improve its properties. We show that the new compounds (R)-3-5Gm and (R)-3-5Gk not only are more potent in vitro than (R)-2-3b ((R)-3-5Aa), but also have molecular weights < 500 g/mol. Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhea. Due to the increased rates of infection as well as the prevalence of multidrug-resistant N. gonorrhoeae strains worldwide, the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) list N. gonorrhoeae at the highest possible threat level to public health. Dual therapy of azithromycin (AZM) and ceftriaxone has been the standard-of-care for treatment of gonococcal infections. However, due to increasing resistance to azithromycin (>33% in some regions) the CDC removed AZM from the treatment regimen for gonorrhea in 2020. Therefore, ceftriaxone remains the only recommended antibiotic for treatment of gonococcal infections. However, increasing resistance to this treatment option has been reported, consequently there is an urgent need to identify novel therapeutics against N. gonorrhoeae. Drug repurposing is a popular strategy that explores new therapeutic opportunities for approved drugs with available information on their pharmacokinetic data, dosages, and toxicity. Salicylic acid is a highly privileged chemical scaffold. Also, the use of salicylic acid to treat sexually transmitted diseases (including gonorrhea) was reported as early as the 19th century. Recently, Dr. Mohamed N. Seleem reported that salicylic acid (4-1a) exhibited modest activity against N. gonorrhoeae strains including the AZM-resistant strain (CDC-181). Chapter 4 of this work illustrates how the anti-gonococcal activity in this scaffold is easily lost by inopportune substitution. However, we found that substituted naphthyl analogs (4-3b,o,p) have superior activity to salicylic acid itself. In addition, the three analogs showed high selectivity, compared to AZM, against N. gonorrhoeae over the vaginal microbiota.en
dc.description.abstractgeneralIn the fight against malaria and gonorrhea, two different diseases, we face one common challenge, which is the emergence of drug resistance towards existing drugs. Therefore, there is a pressing need for new antimalarial and anti-gonorrhea compounds with novel mechanisms of action. This dissertation encompasses my research on the investigation and optimization of the antimalarial candidate (±)-2-3b and Salicylic acid (4-1a) as anti-gonorrhea treatment. Malaria is a life-threatening mosquito-borne disease. It is transmitted through the bites of infected female Anopheles mosquitoes. In 2021, there were 247 million cases of malaria and the estimated number of malaria deaths stood at 619,000. Children under 5 accounted for about 80% of all malaria deaths. In the Carlier group, compound 2-1 (MMV008138) was identified and thoroughly studied as antimalaria candidate. It was found to be effective in killing the malaria parasite, P. falciparum, in red blood cells, in vitro. However, when tested on P. berghei mouse model of malaria, it was found not effective. Chapter 2 of this work discusses the discovery of (±)-2-3b after searching for a structurally similar analog of 2-1. The compound (±)-2-3b can exist in two distinct spatial arrangements (enantiomers) R and S. After preparation of pure enantiomers, we confirmed the pharmacological superiority of (R)-2-3b over (S)-2-3b. The compound (R)-2-3b showed good activity in vitro against malarial parasites P. falciparum, and low general cytotoxicity. However when tested orally on P. berghei mouse model of malaria, it was found not effective. We concluded that the lack of oral efficacy of (R)-2-3b was due to its poor drug-like qualities, such as high molecular weight and low solubility. Chapter 3 of this work explore modifications of (R)-2-3b ((R)-3-5Aa) that will improve its properties. We show that the new compounds (R)-3-5Gm and (R)-3-5Gk not only are more active in vitro than (R)-2-3b ((R)-3-5Aa), but also have lower molecular weights (< 500 g/mol). Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhea. The World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) list N. gonorrhoeae at the highest possible threat level to public health because of the increased rates of infection and the appearance of multidrug-resistant N. gonorrhoeae strains worldwide. Dual therapy of azithromycin (AZM) and ceftriaxone has been the standard-of-care for treatment of gonococcal infections. However, due to increasing resistance to azithromycin the CDC removed AZM from the treatment regimen. Therefore, ceftriaxone remains the only recommended antibiotic for treatment of gonococcal infections. However, increasing resistance to this treatment option has been reported. Drug repurposing is a popular strategy that explores new therapeutic opportunities for approved drugs with available information on their pharmacokinetic data, dosages, and toxicity. Salicylic acid is a highly privileged chemical scaffold that has been used to treat sexually transmitted diseases (including gonorrhea) since the 19th century. Chapter 4 of this work illustrates our efforts to enhance the potency of salicylic acid (4- 1a). I performed chemical modifications on (4-1a) and concluded that anti-gonococcal activity is easily lost by inopportune substitution. However, we found that substituted naphthyl analogs (4-3b,o,p) have superior activity to salicylic acid itself. In addition, the three analogs showed high selectivity, compared to AZM, against N. gonorrhoeae over the vaginal microbiota.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:37187en
dc.identifier.urihttp://hdl.handle.net/10919/115056en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectSynthesisen
dc.subjectPlasmodiumen
dc.subjectDMPKen
dc.subjectin vivoen
dc.subjectMalaria Boxen
dc.subjectanalog by catalogen
dc.subjectNeisseria gonorrhoeaeen
dc.subjectrepurposing.en
dc.titleOptimization of Enantiopure tetrahydro-β-carbolines as Potent Antimalarials and Exploration of salicylic acid analogs for combating multidrug-resistant Neisseria gonorrhoeaeen
dc.typeDissertationen
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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