Mohammad Tasyriq Che Omar

A preliminary study showed that an ethyl acetate extract of the bark from Beilschmiedia lumutensis (Lauraceae family) exhibited promising inhibition activities against α-amylase and α-glucosidase by in vitro assays. Subsequently, this extract revealed three new cyclic polyketides endiandric acids, namely lumutensic acid A-C (1–3). Their structures were elucidated by 1D and 2D NMR, FT-IR, HRESIMS spectroscopic data analysis and by comparison with literature data. The molecular docking study showed that lumutensic acid C (3) showed the highest binding affinity and stability with both enzymes, with strong hydrogen bonding and hydrophobic interactions, outperfoming the standard drug acarbose. These findings suggest that compound 3 could be a promising candidate for anti-hyperglycemic therapeutic development, providing further insight into the potential of B. lumutensis as a source of bioactive compounds.

A series of new dispiropyrrolidine oxindole derivatives (8-10) were successfully synthesised with yield of 57 to 95% via one-pot 1,3-dipolar cycloaddition reaction of azomethine ylides and characterised by various spectroscopic techniques such as NMR, FT-IR, and HRMS. The compounds were evaluated for their activity against methicillin-resistance Staphylococcus aureus (MRSA). Among the compounds, compound 9f and 9g exhibit moderate activity against MRSA with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 250 µg/mL and 325 µg/mL, respectively. The binding energies and interactions of both compounds with S. aureus adhesion proteins such as sdrE, CIfA and FnBPA were further studied through molecular docking studies. Compound 9f (-8.5 ± 0.00 kcal/mol) showed a strong binding affinity than compound 9g (-7.5 ± 0.20 kcal/mol) particularly towards FnBPA adhesion protein. The molecular docking results revealed that the interactions between the compounds 9f and 9g with target proteins correlate with the observed MRSA inhibitory activity, highlighting their potential as promising lead candidates for anti-MRSA drug development.

In search for novel antidiabetic agents, a new series of substituted 2-benzylidene-1-indanone derivatives were synthesized via crossed Adol condensation reaction. The structures of the synthesized compounds were determined using various spectroscopic techniques, including HREIMS, FTIR, and NMR. The enzyme inhibitory activities of the target analogues were assessed using in vitro assays. The tested compounds demonstrated inhibitory potential against α-amylase, as indicated by their IC50 values ranging from 17.7 to 28.2 µM as compared to standard drug acarbose with IC50 value of 30.2 ± 1.9 µM. Furthermore, molecular docking study was conducted to elucidate the binding interactions of the compounds within the α-amylase enzyme binding pocket (PDB ID 2QV4). The results of molecular docking studies indicated that compounds 3m, 3c, 3d has the lowest binding energy (-9.8, -9.3 and -9.4, respectively). The structure-activity relationship (SAR) analysis revealed that alteration in the inhibitory activities of α-amylase enzymes was provided by distinct types of substituents attached to either ortho- or para positions of the phenyl group. The combined SAR and docking results highlight the importance of para-position substitution on ring A for optimal activity, particularly when introducing moderately electron-withdrawing groups such as chlorine, fluorine, and bromine. Thus, in the pursuit of developing newer antidiabetic agents, the in silico ADME prediction was carried out with promising physicochemical, drug likeness and ADME properties which indicated that some compounds were considered drug-like as they do not vio­late any of the rule-based filters of Lipinski.

Colorectal cancer (CRC) is a leading global malignancy, with many stage IV cases requiring surgery and chemotherapy. However, chemoresistance limits treatment efficacy. Targeting resistance pathways such as CXCR2 with therapeutic antibodies offers a promising solution. This study harnessed deep mutational scanning guided by modified heated coarse-grained molecular dynamics (CGMD) simulations, to enhance the binding affinity of the HY29-1 antibody toward CXCR2. The structural stability and intermolecular binding of the variable heavy (vH) and light (vL) chains of the HY29-1 antibody fragment (Fv-HY29-1) alone and complexed with CXCR2 were assessed using modified heated CGMD simulations under thermal stress conditions. Using a modified heated CGMD protocol, the Fv-HY29-1 antibody fragment, modeled via ClusPro (C7) exhibited remarkable conformational stability, maintaining complete (100%) complexation with CXCR2 over a 70 ns simulation. Meanwhile, a benchmark model of the established Fv-Fab14-canine parvovirus capsid complex retained 100% stability under similar conditions. Extended deep mutational scanning over a 1000 ns trajectory pinpointed critical framework residues in the vL chain (A43, L47, and F98) as key determinants of paratope-epitope binding. Rational substitutions (A43P, L47V, F98W) significantly enhanced binding affinity, improving from -36.02 kcal/mol to -94.09 kcal/mol, approximately two-fold increase in binding strength. This marked affinity gain translated into strengthened CXCR2 engagement, highlighting the promise of structure-guided antibody engineering in optimizing therapeutic interactions. This study demonstrated that a 1 μs modified heated simulation with coarse-grained models and deep mutational scanning enables cost-effective optimization of antibody binding affinity and will guide future design of high-affinity antibodies across diverse antigen targets.

In view of the emergence of drug-resistant strains of Plasmodium falciparum, there is an urgent need for the development of new effective antimalarial agents to mitigate the issue of drug resistance. In this study, a series of lupeol (2) and betulin (3) derivatives were synthesised, characterised and evaluated for their antimalarial activity against the P. falciparum FCR3 strain. Eight compounds, including lupenone (1), displayed good anti-plasmodial potency with IC₅₀ values ranging from 0.03-9.9 µM. Moreover, in vitro results showed that compound 1 and derivatives 4a and 4b were the most active compounds with potent inhibitory activity of (0.3 ± 0.3, 0.03 ± 0.05 and 0.7 ± 0.8 μM), respectively, compared to the reference drugs artemisinin and chloroquine (0.7 ± 0.3 and 10.3 ± 2.9 μM), respectively. Furthermore, molecular docking analysis of these compounds revealed good affinity to the binding site of the P. falciparum protein of the PfATP6 with a binding affinity between -9.8 and -8.4 kcal mol^-1via multiple hydrophobic interactions with the amino acid of the PfATP6 protein. The results showed hydrogen bonds and various hydrophobic interactions between the studied compounds and the amino acid of the PfATP6 protein, such as ASN1039, VAL984, ILE981 and ILE1041. Therefore, these compounds could be promising lead structures for further validation as potential candidates in developing new antimalarial drugs.

Six benzhydrol analogues were successfully synthesised and evaluated for their antiproliferative effect on breast cancer cells. These compounds were designed based on the structure of 1´-acetoxychavicol acetate (ACA) and 1´-acetoxyeugenol acetate (AEA), which known for their anticancer properties. Among them, compounds 3b, 3e, and 3f demonstrated significant activity against MCF-7 and MDA-MB-231 breast cancer cell lines (between 5.5-6.0 µM and 1.1-7.0 µM, respectively), outperforming tamoxifen as the standard control. Molecular docking studies revealed that compounds 3b, 3e, and 3f shows good binding energies ranging from ˗5.13 to ˗7.27 kcal/mol with Nuclear Factor-KappaB Kinase alpha (IκBα) protein (PDB ID: 1NFI), compared to ˗5.27 kcal/mol for tamoxifen (control). 3b and 3f interact with IκBα at several residues including APE77, VAL93, and VAL97. The SwissADME and toxicity prediction analysis indicates that three compounds (3b, 3e, and 3f) adhere to the principles of drug-likeness. These findings suggest that the benzhydrol analogues, particularly 3b, 3e, and 3f, could be promising lead for further development as anticancer agents.

Due to the recent emergence of drug-resistance of antidiabetic drugs and increase in the number of diabetes cases around the world, the search for and discovery of more effective α-amylase inhibitors is of great interest. In the present study, a new series of eighteen ortho-carboxamidostilbene derivatives were synthesized via Heck coupling reaction. The structures of the synthesized compounds were identified by various spectroscopic techniques, including HRMS, FTIR and 1D-NMR. In addition, the compounds were evaluated in vitro for their potential α-amylase inhibitory potency using acarbose as the reference drug. Compounds 5e, 5f and 6e showed remarkably moderate to good inhibitory activity with IC50 values ranging from 13.3 − 28.2 µM. These compounds showed the potent IC50 values compared to the reference drug acarbose (IC50 = 30.2 ± 0.1). The in-silico molecular docking studies revealed that the binding interactions of the most active ortho-carboxamidostilbene derivatives (5e and 6e) with binding energies of -8.7 ± 0.0 and -8.6 ± 0.2 kcal/mol. Based on the structure-activity relationship (SAR) analysis, it was established that variations in the inhibitory activities of α-amylase enzymes were attributed to distinct types of substituents at the amide group of aryl ring A, and the number and position of methoxy groups attached to aryl ring B. These findings highlight α-amylase inhibitory properties of ortho-carboxamidostilbene-containing cyclohexyl and benzyl moieties, serving as potential lead compounds in antidiabetic drug development for the treatment of type II diabetes mellitus.

New phenylisoxazole quinoxalin-2-amine hybrids 5a–i were successfully synthesised with yields of 53–85% and characterised with various spectroscopy methods. The synthesised hybrids underwent in vitro α-amylase and α-glucosidase inhibitory assays, with acarbose as the positive control. Through the biological study, compound 5h exhibits the highest α-amylase inhibitory activity with IC₅₀ = 16.4 ± 0.1 μM while compounds 5a–c, 5e and 5h exhibit great potential as α-glucosidase inhibitors, with 5c being the most potent (IC₅₀ = 15.2 ± 0.3 μM). Among the compounds, 5h exhibits potential as a dual inhibitor for both α-amylase (IC₅₀ = 16.4 ± 0.1 μM) and α-glucosidase (IC₅₀ = 31.6 ± 0.4 μM) enzymes. Through the molecular docking studies, the inhibition potential of the selected compounds is supported. Compound 5h showed important interactions with α-amylase enzyme active sites and exhibited the highest binding energy of −8.9 ± 0.10 kcal mol⁻¹, while compound 5c exhibited the highest binding energy of −9.0 ± 0.20 kcal mol⁻¹ by forming important interactions with the α-glucosidase enzyme active sites. The molecular dynamics study showed that the selected compounds exhibited relative stability when binding with α-amylase and α-glucosidase enzymes. Additionally, compound 5h demonstrated a similar pattern of motion and mechanism of action as the commercially available miglitol.