Chemist from Zambia working to discover new drugs in South Africa. #chibale the rest of Africa needs you. #kellychibale

Isoindolines and Isoindoline-1,3-diones as Nonpeptide ACE Inhibitors: An In Silico and In Vitro Modeling Approach Hypertension, a major cardiovascular risk factor, is often treated with peptide-derived angiotensin-converting enzyme inhibitors (ACEi), which can have several side effects. This study examined a new alternative: isoindoline and isoindoline-1,3-dione derivatives as nonpeptide ACE inhibitors. The synthesis and testing of these compounds involved both in silico molecular docking studies and optimized in vitro inhibitory kinetic assays, along with acute toxicity tests in mice. isoindoline-1,3-dione, D-05, demonstrated the strongest ACE inhibition in vitro (IC50 = 416.4 μM) and effectively bound to the enzyme’s catalytic active site in silico. Additionally, isoindoline-1,3-diones showed lower toxicity in mice (LD50 > 1600 mg/kg) compared to isoindolines (LD50 < 1000 mg/kg). This reduced toxicity is attributed to the presence of fewer reactive secondary metabolites. These promising results highlight the potential of isoindoline-1,3-diones as innovative nonpeptide ACE inhibitors and support further in vivo studies to verify their antihypertensive effects.

Isoindolines and Isoindoline-1,3-diones as Nonpeptide ACE Inhibitors: An In Silico and In Vitro Modeling Approach

pubs.acs.org/doi/10.1021/...

#KellyChibale #MedicinalChemistry #Hypertension #CardiovascularResearch #ACEInhibitors #DrugDiscovery #ComputationalChemistry

Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity and Reduced Mitochondrial Inhibition–Associated Toxicity Niclosamide, an FDA-approved anthelmintic, functions as a mitochondrial uncoupler with promising anticancer potential, yet its efficacy remains limited, often ascribed to poor bioavailability. We iden...

Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity and Reduced Mitochondrial Inhibition–Associated Toxicity
pubs.acs.org/doi/10.1021/...

#KellyChibale #MedicinalChemistry #CancerResearch #MitochondrialBiology #OncologyResearch #DrugDiscovery #QSAR

Maltose-Conjugated Thiosemicarbazones from Substituted Benzaldehydes: Synthesis and Inhibitory Activity against Gram-(+) and Gram-(−) Bacteria The increasing prevalence of multidrug-resistant bacteria necessitates the development of new antibacterial scaffolds with improved efficacy and safety. Thiosemicarbazones are known for their diverse ...

Maltose-Conjugated Thiosemicarbazones from Substituted Benzaldehydes: Synthesis and Inhibitory Activity against Gram-(+) and Gram-(−) Bacteria
pubs.acs.org/doi/10.1021/...

#KellyChibale #MedicinalChemistry #AntimicrobialResistance #AntibioticDiscovery #InfectiousDiseases #ChemicalBiology

Now also an Honorary Fellow of the #RoyalSocietyofChemistry, its highest accolade. Encouraging to see recognition of science that combines excellence, leadership and societal impact. Read more: www.rsc.org/news/2026-ho... #KellyChibale #HonoraryFellow #ChemicalSciences #H3D #GlobalScience

Design, Synthesis, and Structure–Activity Relationship Studies of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as Potent Casein Kinase 1α (CK1α) Inhibitors @acs.org pubs.acs.org/doi/10.1021/...

#KellyChibale #CancerResearch #Leukaemia #TargetedTherapy #KinaseInhibitors #MedicinalChemistry #DrugDiscovery

Characterization of the Formation of the Acyl Glucuronide Metabolite of 7-Carboxy-Cannabidiol in Human Liver, Kidney, and Intestinal Microsomes and In Vivo in Mice Acyl glucuronides are common metabolites of carboxylic acids. They can be reactive and cause adverse events. The acyl glucuronide metabolite of delta-9-tetrahydrocannabinol (THC) is abundant in humans after THC consumption but acyl glucuronide formation from the cannabidiol (CBD) metabolite 7-carboxy-cannabidiol (7-COOH-CBD) has not been previously described. Here, we identified and characterized both acyl and phenolic glucuronides of 7-COOH-CBD formed in human liver, kidney, and intestinal microsomes. The 7-COOH-CBD-acyl-glucuronide was mostly formed by UGT1A1 and UGT1A3, while the 7-COOH-CBD-phenolic-glucuronide was formed by UGT1A9. 7-COOH-CBD-acyl-glucuronide formation was also detected in vivo in mice. 7-COOH-CBD-acyl-glucuronide showed extensive acyl migration while 11-COOH-THC-glucuronide did not. Human serum albumin enhanced migration, while liver fatty acid binding protein (FABP1) protected against 7-COOH-CBD-acyl-glucuronide migration. When corrected for unbound fraction, FABP1 increased 7-COOH-CBD glucuronidation efficiency. These findings suggest that 7-COOH-CBD-acyl-glucuronide is a metabolite of CBD in humans and may play a role in CBD related liver toxicity.

Characterization of the Formation of the Acyl Glucuronide Metabolite of 7-Carboxy-Cannabidiol in Human Liver, Kidney, and Intestinal Microsomes and In Vivo in Mice pubs.acs.org/doi/10.1021/... @acs.org

#KellyChibale #DrugMetabolism #LiverToxicity #Pharmacokinetics #MedicinalChemistry #DrugSafety

AI-Assisted Discovery and Optimization of Small-Molecule TREM2 Agonists with Functional Microglial Activity Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose loss-of-function variants increase Alzheimer’s disease (AD) risk. While antibody-based agonists have sho...

AI-Assisted Discovery and Optimization of Small-Molecule TREM2 Agonists with Functional Microglial Activity pubs.acs.org/doi/10.1021/... @acs.org

#KellyChibale #AlzheimersDisease #Neurodegeneration #AIDrugDiscovery #MedicinalChemistry #Neuroscience #DrugDiscovery

Discovery and Characterization of Zilurgisertib, a Potent and Selective Inhibitor of Activin Receptor-like Kinase-2 (ALK2) for the Treatment of Fibrodysplasia Ossificans Progressiva Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease leading to progressive soft tissue heterotopic ossification (HO) with no curative treatment available to date. It is caused by gain-of-function mutations in the activin A type-1 receptor ACVR1/ALK2, a member of the bone morphogenetic protein (BMP) type I receptor family. Most recent clinical trials in FOP have adopted for the first time on-target therapies to normalize the aberrant ALK2 receptor activity. Here we describe the discovery and preclinical characterization of zilurgisertib, a novel small-molecule inhibitor of ALK2 kinase with high biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and excellent oral bioavailability in preclinical species. Zilurgisertib fully suppresses HO in a pediatric mouse model of injury-induced FOP and therefore holds great potential as a novel targeted disease-modifying therapy for FOP. The candidate is being evaluated in clinical trials.

Zilurgisertib, a potent, selective ALK2 inhibitor, blocks aberrant signalling and prevents heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) models and is now advancing as a first-in-class, disease-modifying therapy @pubs.acs.org pubs.acs.org/doi/10.1021/... #KellyChibale

Discovery of a Novel G9a-Selective Inhibitor for Hepatocellular Carcinoma Treatment Epigenetic dysregulation, particularly aberrant histone methylation orchestrated by histone methyltransferases (HMTs), is a fundamental driver of hepatocellular carcinoma (HCC). Among these HMTs, H3K9-specific methyltransferase G9a is markedly upregulated and promotes tumorigenesis. However, current G9a inhibitors lack sufficient selectivity and potency. Here, we identified compound 1071, a novel selective G9a inhibitor with a distinct chemical scaffold, which demonstrates superior cellular activity compared with the existing G9a inhibitor UNC0638. Mechanistically, compound 1071 reduces H3K9me2 levels and modulates the expression of key G9a targets, including p21, FOXO1, and PD-L1. Moreover, compound 1071 exhibits potent antitumor activity in both subcutaneous and c-Myc-driven HCC models, outperforming the first-line drug sorafenib without significant toxicity. This study establishes compound 1071 as a promising lead for G9a-targeted HCC therapy, advancing epigenetic drug discovery.

Epigenetic dysregulation drives hepatocellular carcinoma via G9a upregulation. In #ACSMedChemLett, Mu et al. report a novel & selective G9a inhibitor that lowers H3K9me2, restores tumour suppressor expression & outperforms sorafenib in models @pubs.acs.org pubs.acs.org/doi/10.1021/...
#KellyChibale

Optimization of Hsp90/Aha1 Small-Molecule Disruptors Via the Evaluation of Amide Bioisosteres Recent structure–activity relationships (SAR) were established around KU-177, the parent scaffold for an Hsp90/Aha1 small-molecule disruptor, which suggested that the central amide linker adopted a ci...

New analogues of the Hsp90/Aha1 disruptor KU-177 reported by Catalfano et al. in #ACSMedChemLett reveal that a cis-amide linker is key for inhibition; a sulfonamide-containing compound showed strong efficacy, solubility & metabolic stability @pubs.acs.org pubs.acs.org/doi/10.1021/...
#KellyChibale

#KellyChibale #AIinScience #Pharmacogenomics #MalariaResearch #TuberculosisResearch #PrecisionMedicine #AfricaScience #GlobalHealth #DrugDiscovery

Honoured to be named an @astmh.bsky.social Distinguished International Fellow and to deliver the Commemorative Lecture at the Closing Plenary in Toronto. Partnership across borders is vital to advancing global health innovation.

🔗 www.astmh.org

#KellyChibale #ASTMH #GlobalHealth #TropicalMedicine

Delivered a seminar at @tsinghuauniversity.bsky.social University where next-gen antimalarials and shared insights from #ACSMedChemLett was discussed. My privilege to engage with global colleagues in science.

🔗https://www.acs.org/about.html

#KellyChibale #MalariaResearch #DrugDiscovery

Africa finally has its own drug-regulation agency — and it could transform the continent’s health If it gets things right, the first major regulator of medicines to launch for 30 years could empower Africa to tackle African challenges around health and disease.

(4/4) Read our full Comment in @Nature: www.nature.com/articles/d41...

#KellyChibale #AfricanMedicinesAgency #PublicHealth #ClinicalResearch #DrugDiscovery #GlobalHealth #AfricaScience #Pharmacogenomics

I have officially been inducted as an International Member of the US National Academy of Medicine. A proud moment for #AfricanLedScience and for the growing recognition of world-class research. www.kellychibale.co.za
#KellyChibale #NAMMember #GlobalHealth #AfricaScience #DrugDiscovery

Proud to close the Science of Malaria Medicines Symposium in Geneva last week. Africa’s growing R&D capacity driving the next century of medicines. Full reflection www.linkedin.com/feed/update/...

#KellyChibale #H3D #H3DFoundation #MedicinesforMalariaVenture #AfricaScience #MalariaResearch

Discovery of VNRX-9945, a Potent, Broadly Active Capsid Assembly Modulator as a Clinical Candidate for the Treatment of Chronic Hepatitis B Virus Infection Targeting the capsid protein of the hepatitis B virus (HBV) has emerged as a promising strategy for developing new antiviral therapies. In this study, we report the discovery of a novel series of pyrrole oxo-carboxamide compounds as HBV capsid assembly modulators (CAMs) that block viral replication. Through a process of focused structure–activity relationship (SAR) optimization, we identified compound 12 (VNRX-9945), which exhibited excellent and broad antiviral activity against multiple HBV genotypes in vitro, along with favorable pharmacokinetic profiles across multiple species. Additionally, 12 demonstrated robust efficacy in the adeno-associated virus mouse model of HBV (AAV-HBV) infection. This compound has advanced into Phase 1 clinical trials to evaluate its safety and pharmacokinetics in healthy volunteers, to enable treatment of chronic HBV infections.

In #ACSMedChemLett Liu et al. report a compound (VNRX-9945) with excellent antiviral activity against multiple #hepatitisBvirus genotypes in vitro, favourable PK profiles across multiple species, and efficacy in a mouse model of disease. pubs.acs.org/doi/10.1021/... #MedicinalChemistry #KellyChibale