A5051128766- Computational Drug Discovery Methods
- Research on Leishmaniasis Studies
- Malaria Research and Control
- Tuberculosis Research and Epidemiology
- Enzyme function and inhibition
- HIV/AIDS drug development and treatment
- Trypanosoma species research and implications
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Cancer therapeutics and mechanisms
- Synthesis and biological activity
- Quinazolinone synthesis and applications
- Synthesis and Catalytic Reactions
University of Cape Town
2017-2025
South African Medical Research Council
2020
Compounds acting on multiple targets are critical to combating antimalarial drug resistance. Here, we report that the human “mammalian target of rapamycin” (mTOR) inhibitor sapanisertib has potent prophylactic liver stage activity, in vitro and vivo asexual blood (ABS) transmission-blocking activity against protozoan parasite Plasmodium spp. Chemoproteomics studies revealed potential kinase targets, inhibition phosphatidylinositol 4-kinase type III beta (PI4Kβ) cyclic guanosine...
New antibiotics with either a novel mode of action or inhibition are urgently needed to overcome the threat drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against Mycobacterium (Mtb), causative agent TB. While clinical candidate zoliflodacin has progressed phase 3 trials for treatment gonorrhea, compounds herein demonstrated higher inhibitory potency Mtb (e.g., compound 42 IC50 = 2.0) and lower minimum...
Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors
Angiotensin-1-converting enzyme (ACE) is a zinc-dependent carboxypeptidase of therapeutic interest for the treatment hypertension, inflammation and fibrosis. It consists two homologous N C catalytic domains, nACE cACE, respectively. Unfortunately, current clinically available ACE inhibitors produce undesirable side effects due to nonselective inhibition these domains. Through structure-based drug design, we previously identified series diprolyl-derived (SG3, SG15, SG16, SG17 SG18) in an...
Plasmodium falciparum phosphatidylinositol 4-kinase (PfPI4K) has emerged as a promising new drug target for novel antimalarial therapeutics. In the absence of reliable high-resolution three-dimensional structure, homology model PfPI4K was built tool structure-based design. This been validated against three distinct chemical series potent inhibitors using docking and energy minimizations to elucidate interactions crucial PI4K inhibition antiplasmodium activity. Despite its potential an...
Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set compounds against Mycobacterium tuberculosis (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 1 as moderately active hit. Structure–activity relationship (SAR) studies demonstrated clear scope to improve potency MIC values <0.5 μM, and plausible pharmacophore model was developed describe the chemical space compounds. Compounds are bactericidal vitro replicating Mtb retained activity...
Angiotensin-I converting enzyme (ACE) is a zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both nonselectively, resulting in adverse effects such as cough angioedema. Selectively inhibiting the individual likely reduce these potentially treat fibrosis addition hypertension. ACEi from GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, diprolyl chemical...
Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive in vitro activity and vivo efficacy mouse models of malaria infection. Herein, we report the synthesis antiplasmodium evaluation a new series amidated analogues demonstrate that these compounds potently inhibit Plasmodium phosphatidylinositol-4-kinase (PI4K) type IIIβ while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) vitro. Using silico docking, predict key...
Alternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain mycolic acids in Mycobacterium tuberculosis (Mtb). Mutations compound 1-resistant Mtb mutants mapped HadC (Rv0637; K157R), while chemoproteomics confirmed compound's binding...