Honors & Awards
U54 Brain MetNet Seed Grant, Stanford Brain Metastasis Consortium (SBMC) (2022)
PhD, University of Burgundy Franche-Comté (France), University of Sfax (Tunisia), Medicinal Chemistry (2019)
Master of Science, University of Reims Champagne-Ardenne (France), Chemistry of Natural Substances and Medicines (2015)
Engineer, National Institute of Applied Sciences and Technology (Tunisia), Industrial Chemistry (2014)
Current Research and Scholarly Interests
My work is focused on the development of small molecules radiotracers for cancer imaging, and small molecules and peptides theranostics for cancer detection, targeted radionuclide therapy, and monitoring of tumor response to therapy.
Development of [18F]DASA-10 for enhanced imaging of pyruvate kinase M2.
Nuclear medicine and biology
2023; 124-125: 108382
The aim of this study was to develop a positron emission tomography (PET) radiotracer for measuring pyruvate kinase M2 (PKM2) with improved physicochemical and pharmacokinetic properties compared to [18F]DASA-23.First, we synthesized [18F]DASA-10 and tested its uptake and retention compared to [18F]DASA-23 in human and mouse glioma cell lines. We then confirmed the specificity of [18F]DASA-10 by transiently modulating the expression of PKM2 in DU145 and HeLa cells. Next, we determined [18F]DASA-10 pharmacokinetics in healthy nude mice using PET imaging and subsequently assessed the ability of [18F]DASA-10 versus [18F]DASA-23 to enable in vivo detection of intracranial gliomas in syngeneic C6 rat models of glioma.[18F]DASA-10 demonstrated excellent cellular uptake and retention with values significantly higher than [18F]DASA-23 in all cell lines and timepoints investigated. [18F]DASA-10 showed a 73 % and 65 % reduced uptake respectively in DU145 and HeLa cells treated with PKM2 siRNA as compared to control siRNA treated cells. [18F]DASA-10 showed favorable biodistribution and pharmacokinetic properties and a significantly improved tumor-to-brain ratio in rat C6 glioma models relative to [18F]DASA-23 (3.2 ± 0.8 versus 1.6 ± 0.3, p = 0.01).[18F]DASA-10 is a new PET radiotracer for molecular imaging of PKM2 with potential to overcome the prior limitations observed with [18F]DASA-23. [18F]DASA-10 shows promise for clinical translation to enable imaging of brain malignancies owing to its low background signal in the healthy brain.
View details for DOI 10.1016/j.nucmedbio.2023.108382
View details for PubMedID 37634399
Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation
2023; 28 (1)
Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.
View details for DOI 10.3390/molecules28010071
View details for Web of Science ID 000910211400001
View details for PubMedID 36615267
View details for PubMedCentralID PMC9822022
New Dual Small Molecules for Alzheimer's Disease Therapy Combining Histamine H-3 Receptor (H3R) Antagonism and Calcium Channels Blockade with Additional Cholinesterase Inhibition
JOURNAL OF MEDICINAL CHEMISTRY
2019; 62 (24): 11416-11422
New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (Ki = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
View details for DOI 10.1021/acs.jmedchem.9b00937
View details for Web of Science ID 000505633400029
View details for PubMedID 31724859
Multi-target 1,4-dihydropyridines showing calcium channel blockade and antioxidant capacity for Alzheimer's disease therapy
2019; 91: 103205
In this work we describe the synthesis, Ca+2 channel blockade capacity and antioxidant power of N3,N5-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxamides 1-9, a number of multi-target small 1,4-dihydropyridines (DHP), designed by juxtaposition of melatonin and nimodipine. As a result, we have identified antioxidant DHP 7 (Ca2+ channel blockade: 55%, and 8.78 Trolox/Equivalents), the most balanced DHP analyzed here, for potential Alzheimer's disease therapy.
View details for DOI 10.1016/j.bioorg.2019.103205
View details for Web of Science ID 000487812000076
View details for PubMedID 31446330
Synthesis and Biological Evaluation of Novel Chromone plus Donepezil Hybrids for Alzheimer's Disease Therapy
CURRENT ALZHEIMER RESEARCH
2019; 16 (9): 815-820
Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets.We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals.We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed.Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits for further development.The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.
View details for DOI 10.2174/1567205016666191011112624
View details for Web of Science ID 000493721100004
View details for PubMedID 31660831
Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer's disease therapy
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
2019; 34 (1): 163-170
In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
View details for DOI 10.1080/14756366.2018.1538136
View details for Web of Science ID 000451541800001
View details for PubMedID 30482062
View details for PubMedCentralID PMC6263107