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Domperidone nanocrystals with boosted oral bioavailability: fabrication, evaluation and molecular insight into the polymer-domperidone nanocrystal interaction

Ndlovu ST, Ullah N, Khan S, Ramharack P, Soliman M, de Matas M, et al.

Drug Deliv Transl Res, 2019 Feb;9(1):284-297.
PMID: 30387048 DOI: 10.1007/s13346-018-00596-w

The aim of this study was to employ experimental and molecular modelling approaches to use molecular level interactions to rationalise the selection of suitable polymers for use in the production of stable domperidone (DOMP) nanocrystals with enhanced bioavailability. A low-energy antisolvent precipitation method was used for the preparation and screening of polymers for stable nanocrystals of DOMP. Ethyl cellulose was found to be very efficient in producing stable DOMP nanocrystals with particle size of 130 ± 3 nm. Moreover, the combination of hydroxypropyl methylcellulose and polyvinyl alcohol was also shown to be better in producing DOMP nanocrystals with smaller particle size (200 ± 3.5 nm). DOMP nanosuspension stored at 2-8 °C and at room temperature (25 °C) exhibited better stability compared to the samples stored at 40 °C. Crystallinity of the unprocessed and processed DOMP was monitored by differential scanning calorimetry and powder X-ray diffraction. DOMP nanocrystals gave enhanced dissolution rate compared to the unprocessed drug substance. DOMP nanocrystals at a dose of 10 mg/kg in rats showed enhanced bioavailability compared to the raw drug substance and marketed formulation. A significant increase in plasma concentration of 2.6 μg/mL with a significant decrease in time (1 h) to reach maximum plasma concentration was observed for DOMP nanocrystals compared to the raw DOMP. Molecular modelling studies provided underpinning knowledge at the molecular level of the DOMP-polymer nanocrystal interactions and substantiated the experimental studies. This included an understanding of the impact of polymers on the size of nanocrystals and their associated stability characteristics.
Designing of promising medicinal scaffolds for Alzheimer's disease through enzyme inhibition, lead optimization, molecular docking and dynamic simulation approaches

Hassan M, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Shahzadi S, Raza H, et al.

Bioorg Chem, 2019 10;91:103138.
PMID: 31446329 DOI: 10.1016/j.bioorg.2019.103138

In the designed research work, a series of 2-furoyl piperazine based sulfonamide derivatives were synthesized as therapeutic agents to target the Alzheimer's disease. The structures of the newly synthesized compounds were characterized through spectral analysis and their inhibitory potential was evaluated against butyrylcholinesterase (BChE). The cytotoxicity of these sulfonamides was also ascertained through hemolysis of bovine red blood cells. Furthermore, compounds were inspected by Lipinki Rule and their binding profiles against BChE were discerned by molecular docking. The protein fluctuations in docking complexes were recognized by dynamic simulation. From our in vitro and in silico results 5c, 5j and 5k were identified as promising lead compounds for the treatment of targeted disease.
Fulltext Design and Evaluation of a Flexible Dual-Band Meander Line Monopole Antenna for On- and Off-Body Healthcare Applications

Ali SM, Sovuthy C, Noghanian S, Ali Z, Abbasi QH, Imran MA, et al.

Micromachines (Basel), 2021 Apr 22;12(5).
PMID: 33922053 DOI: 10.3390/mi12050475

The human body is an extremely challenging environment for wearable antennas due to the complex antenna-body coupling effects. In this article, a compact flexible dual-band planar meander line monopole antenna (MMA) with a truncated ground plane made of multiple layers of standard off-the-shelf materials is evaluated to validate its performance when worn by different subjects to help the designers who are shaping future complex on-/off-body wireless devices. The antenna was fabricated, and the measured results agreed well with those from the simulations. As a reference, in free-space, the antenna provided omnidirectional radiation patterns (ORP), with a wide impedance bandwidth of 1282.4 (450.5) MHz with a maximum gain of 3.03 dBi (4.85 dBi) in the lower (upper) bands. The impedance bandwidth could reach up to 688.9 MHz (500.9 MHz) and 1261.7 MHz (524.2 MHz) with the gain of 3.80 dBi (4.67 dBi) and 3.00 dBi (4.55 dBi), respectively, on the human chest and arm. The stability in results shows that this flexible antenna is sufficiently robust against the variations introduced by the human body. A maximum measured shift of 0.5 and 100 MHz in the wide impedance matching and resonance frequency was observed in both bands, respectively, while an optimal gap between the antenna and human body was maintained. This stability of the working frequency provides robustness against various conditions including bending, movement, and relatively large fabrication tolerances.
Correction to: Domperidone nanocrystals with boosted oral bioavailability: fabrication, evaluation and molecular insight into the polymer-domperidone nanocrystal interaction

Ndlovu ST, Ullah N, Khan S, Ramharack P, Soliman M, de Matas M, et al.

Drug Deliv Transl Res, 2024 Feb 28.
PMID: 38416387 DOI: 10.1007/s13346-024-01554-5
Fulltext Convergent synthesis, kinetics insight and allosteric computational ascriptions of thiazole-(5-aryl)oxadiazole hybrids embraced with propanamides as alkaline phosphatase inhibitors

Butt ARS, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Muhammad S, Raza H, et al.

RSC Adv, 2023 May 02;13(20):13798-13808.
PMID: 37197574 DOI: 10.1039/d3ra01348k

Considering the varied pharmacological prominence of thiazole and oxadiazole heterocyclic moieties, a unique series of bi-heterocyclic hybrids, 8a-h, was synthesized in a convergent manner. The structures of newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, and IR spectral studies. The structure-activity relationship of these compounds was predicted by examining their inhibitory effects against alkaline phosphatase, whereby all these molecules exhibited superb inhibitory potentials relative to the standard used. The kinetics mechanism was determined by Lineweaver-Burk plots which revealed that 8g inhibited the studied enzyme non-competitively by forming an enzyme-inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 0.42 μM. The allosteric computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal mol-1). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules have potential to be nontoxic medicinal scaffolds for the treatment of alkaline phosphate-associated ailments.
Fulltext Comprehensive computational target fishing approach to identify Xanthorrhizol putative targets

Shahid M, Azfaralariff A, Law D, Najm AA, Sanusi SA, Lim SJ, et al.

Sci Rep, 2021 01 15;11(1):1594.
PMID: 33452398 DOI: 10.1038/s41598-021-81026-9

Xanthorrhizol (XNT), is a bioactive compound found in Curcuma xanthorrhiza Roxb. This study aimed to determine the potential targets of the XNT via computational target fishing method. This compound obeyed Lipinski's and Veber's rules where it has a molecular weight (MW) of 218.37 gmol-1, TPSA of 20.23, rotatable bonds (RBN) of 4, hydrogen acceptor and donor ability is 1 respectively. Besides, it also has half-life (HL) values 3.5 h, drug-likeness (DL) value of 0.07, oral bioavailability (OB) of 32.10, and blood-brain barrier permeability (BBB) value of 1.64 indicating its potential as therapeutic drug. Further, 20 potential targets were screened out through PharmMapper and DRAR-CPI servers. Co-expression results derived from GeneMANIA revealed that these targets made connection with a total of 40 genes and have 744 different links. Four genes which were RXRA, RBP4, HSD11B1 and AKR1C1 showed remarkable co-expression and predominantly involved in steroid metabolic process. Furthermore, among these 20 genes, 13 highly expressed genes associated with xenobiotics by cytochrome P450, chemical carcinogenesis and steroid metabolic pathways were identified through gene ontology (GO) and KEGG pathway analysis. In conclusion, XNT is targeting multiple proteins and pathways which may be exploited to shape a network that exerts systematic pharmacological effects.
Fulltext Chimeric Plasmodium falciparum parasites expressing Plasmodium vivax circumsporozoite protein fail to produce salivary gland sporozoites

Marin-Mogollon C, van Pul FJA, Miyazaki S, Imai T, Ramesar J, Salman AM, et al.

Malar J, 2018 Aug 09;17(1):288.
PMID: 30092798 DOI: 10.1186/s12936-018-2431-1

BACKGROUND: Rodent malaria parasites where the gene encoding circumsporozoite protein (CSP) has been replaced with csp genes from the human malaria parasites, Plasmodium falciparum or Plasmodium vivax, are used as pre-clinical tools to evaluate CSP vaccines in vivo. These chimeric rodent parasites produce sporozoites in Anopheles stephensi mosquitoes that are capable of infecting rodent and human hepatocytes. The availability of chimeric P. falciparum parasites where the pfcsp gene has been replaced by the pvcsp would open up possibilities to test P. vivax CSP vaccines in small scale clinical trials using controlled human malaria infection studies.
METHODS: Using CRISPR/Cas9 gene editing two chimeric P. falciparum parasites, were generated, where the pfcsp gene has been replaced by either one of the two major pvcsp alleles, VK210 or VK247. In addition, a P. falciparum parasite line that lacks CSP expression was also generated. These parasite lines have been analysed for sporozoite production in An. stephensi mosquitoes.
RESULTS: The two chimeric Pf-PvCSP lines exhibit normal asexual and sexual blood stage development in vitro and produce sporozoite-containing oocysts in An. stephensi mosquitoes. Expression of the corresponding PvCSP was confirmed in oocyst-derived Pf-PvCSP sporozoites. However, most oocysts degenerate before sporozoite formation and sporozoites were not found in either the mosquito haemocoel or salivary glands. Unlike the chimeric Pf-PvCSP parasites, oocysts of P. falciparum parasites lacking CSP expression do not produce sporozoites.
CONCLUSIONS: Chimeric P. falciparum parasites expressing P. vivax circumsporozoite protein fail to produce salivary gland sporozoites. Combined, these studies show that while PvCSP can partially complement the function of PfCSP, species-specific features of CSP govern full sporozoite maturation and development in the two human malaria parasites.
Challenges and recent trends with the development of hydrogel fiber for biomedical applications

Ansar R, Saqib S, Mukhtar A, Niazi MBK, Shahid M, Jahan Z, et al.

Chemosphere, 2022 Jan;287(Pt 1):131956.
PMID: 34523459 DOI: 10.1016/j.chemosphere.2021.131956

Hydrogel is the most emblematic soft material which possesses significantly tunable and programmable characteristics. Polymer hydrogels possess significant advantages including, biocompatible, simple, reliable and low cost. Therefore, research on the development of hydrogel for biomedical applications has been grown intensely. However, hydrogel development is challenging and required significant effort before the application at an industrial scale. Therefore, the current work focused on evaluating recent trends and issues with hydrogel development for biomedical applications. In addition, the hydrogel's development methodology, physicochemical properties, and biomedical applications are evaluated and benchmarked against the reported literature. Later, biomedical applications of the nano-cellulose-based hydrogel are considered and critically discussed. Based on a detailed review, it has been found that the surface energy, intermolecular interactions, and interactions of hydrogel adhesion forces are major challenges that contribute to the development of hydrogel. In addition, compared to other hydrogels, nanocellulose hydrogels demonstrated higher potential for drug delivery, 3D cell culture, diagnostics, tissue engineering, tissue therapies and gene therapies. Overall, nanocellulose hydrogel has the potential for commercialization for different biomedical applications.
Bi-heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Abbasi MA, Nazir M, Ur-Rehman A, Siddiqui SZ, Hassan M, Raza H, et al.

Arch Pharm (Weinheim), 2019 Mar;352(3):e1800278.
PMID: 30624805 DOI: 10.1002/ardp.201800278

Novel bi-heterocyclic benzamides were synthesized by sequentially converting 4-(1H-indol-3-yl)butanoic acid (1) into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3), and a nucleophilic 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a-k) with 4-(chloromethyl)benzoylchloride (6) to afford 4-(chloromethyl)-N-(substituted-phenyl)benzamides (7a-k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a-k, to acquire the targeted bi-heterocyclic benzamides, 8a-k. The structural confirmation of all the synthesized compounds was done by IR, 1 H NMR, 13 C NMR, EI-MS, and CHN analysis data. The inhibitory effects of these bi-heterocyclic benzamides (8a-k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver-Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non-competitively to form an enzyme-inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.
Fulltext Author Correction: The Plasmodium falciparum male gametocyte protein P230p, a paralog of P230, is vital for ookinete formation and mosquito transmission

Marin-Mogollon C, van de Vegte-Bolmer M, van Gemert GJ, van Pul FJA, Ramesar J, Othman AS, et al.

Sci Rep, 2019 May 03;9(1):7061.
PMID: 31053746 DOI: 10.1038/s41598-019-43505-y

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Fulltext Anti-breast cancer synthetic peptides derived from the Anabas testudineus skin mucus fractions

Najm AAK, Azfaralariff A, Dyari HRE, Othman BA, Shahid M, Khalili N, et al.

Sci Rep, 2021 11 30;11(1):23182.
PMID: 34848729 DOI: 10.1038/s41598-021-02007-6

Previous study has shown the antimicrobial activities of mucus protein extracted from Anabas testudineus. In this study, we are interested in characterizing the anticancer activity of the A. testudineus antimicrobial peptides (AMPs). The mucus was extracted, fractioned, and subjected to antibacterial activity testing to confirm the fish's AMPs production. The cytotoxic activity of each fraction was also identified. Fraction 2 (F2), which shows toxicity against MCF7 and MDA-MB-231 were sent for peptide sequencing to identify the bioactive peptide. The two peptides were then synthetically produced and subjected to cytotoxic assay to prove their efficacy against cancer cell lines. The IC50 for AtMP1 against MCF7 and MDA-MB-231 were 8.25 ± 0.14 μg/ml and 9.35 ± 0.25 μg/ml respectively, while for AtMP2 it is 5.89 ± 0.14 μg/ml and 6.97 ± 0.24 μg/ml respectively. AtMP1 and AtMP2 treatment for 48 h induced breast cancer cell cycle arrest and apoptosis by upregulating the p53, which lead to upregulate pro-apoptotic BAX gene and downregulate the anti-apoptotic BCL-2 gene, consequently, trigger the activation of the caspase-3. This interaction was supported by docking analysis (QuickDBD, HPEPDOCK, and ZDOCK) and immunoprecipitation. This study provided new prospects in the development of highly effective and selective cancer therapeutics based on antimicrobial peptides.
Fulltext A P. falciparum NF54 Reporter Line Expressing mCherry-Luciferase in Gametocytes, Sporozoites, and Liver-Stages

Marin-Mogollon C, Salman AM, Koolen KMJ, Bolscher JM, van Pul FJA, Miyazaki S, et al.

Front Cell Infect Microbiol, 2019;9:96.
PMID: 31058097 DOI: 10.3389/fcimb.2019.00096

Transgenic malaria parasites expressing fluorescent and bioluminescent proteins are valuable tools to interrogate malaria-parasite biology and to evaluate drugs and vaccines. Using CRISPR/Cas9 methodology a transgenic Plasmodium falciparum (Pf) NF54 line was generated that expresses a fusion of mCherry and luciferase genes under the control of the Pf etramp10.3 gene promoter (line mCherry-luc@etramp10.3). Pf etramp10.3 is related to rodent Plasmodium uis4 and the uis4 promoter has been used to drive high transgene expression in rodent parasite sporozoites and liver-stages. We examined transgene expression throughout the complete life cycle and compared this expression to transgenic lines expressing mCherry-luciferase and GFP-luciferase under control of the constitutive gapdh and eef1a promoters. The mCherry-luc@etramp10.3 parasites express mCherry in gametocytes, sporozoites, and liver-stages. While no mCherry signal was detected in asexual blood-stage parasites above background levels, luciferase expression was detected in asexual blood-stages, as well as in gametocytes, sporozoites and liver-stages, with the highest levels of reporter expression detected in stage III-V gametocytes and in sporozoites. The expression of mCherry and luciferase in gametocytes and sporozoites makes this transgenic parasite line suitable to use in in vitro assays that examine the effect of transmission blocking inhibitors and to analyse gametocyte and sporozoite biology.
2-Furoic piperazide derivatives as promising drug candidates of type 2 diabetes and Alzheimer's diseases: In vitro and in silico studies

Abbasi MA, Hassan M, Ur-Rehman A, Siddiqui SZ, Hussain G, Shah SAA, et al.

Comput Biol Chem, 2018 Dec;77:72-86.
PMID: 30245349 DOI: 10.1016/j.compbiolchem.2018.09.007

The heterocyclic compounds have been extensively reported for their bioactivity potential. The current research work reports the synthesis of some new multi-functional derivatives of 2-furoic piperazide (1; 1-(2-furoyl)piperazine). The synthesis was initiated by reacting the starting compound 1 with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2) in a basic, polar and protic medium to obtain the parent sulfonamide 3 which was then treated with different electrophiles, 4a-g, in a polar and aprotic medium to acquire the designed molecules, 5a-g. These convergent derivatives were evaluated for their inhibitory potential against α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Acarbose was used as a reference standard for α-glucosidase inhibition while eserine for AChE and BChE inhibition. Some of the synthesized compounds were identified as promising inhibitors of these three enzymes and their bioactivity potentials were also supported by molecular docking study. The most active compounds among the synthetic analogues might be helpful in drug discovery and development for the treatment of type 2 diabetes and Alzhiemer's diseases.

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