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Synthesis, spectral characterisation, biocidal investigation, in-silico and molecular docking studies of 4-[(2-chloro-4-methylphenyl)carbamoyl]butanoic acid derived triorganotin(IV) compounds

Hanifa B, Bibi N, Sirajuddin M, Tiekink ERT, Kubicki M, Khan I, et al.

J Biomol Struct Dyn, 2024;42(4):1826-1845.
PMID: 37114651 DOI: 10.1080/07391102.2023.2204160

Three triorganotin(IV) compounds, R3Sn(L), with R = CH3 (1), n-C4H9 (2) and C6H5 (3), and LH = 4-[(2-chloro-4-methylphenyl)carbamoyl]butanoic acid, were prepared and confirmed by various techniques. A five-coordinate, distorted trigonal-bipyramidal geometry was elucidated for tin(IV) centres both in solution and solid states. An intercalation mode was confirmed for the compound SS-DNA interaction by UV-visible, viscometric techniques and molecular docking. MD simulation revealed stable binding of LH with SS-DNA. Anti-bacterial investigation revealed 2 to be generally the most potent, especially against Sa and Ab, i.e. having the lowest MIC values (≤0.25 μg/mL) compared to the standard anti-biotics vancomycin-HCl (MIC = 1 μg/mL) and colistin-sulphate (MIC = 0.25 μg/mL). Similarly, the anti-fungal profile shows 2 exhibits 100% inhibition against Ca and Cn fungal strains and has MIC values (≤0.25 μg/mL) comparatively lower than standard drug fluconazole (0.125 and 8 μg/mL for Ca and Cn, respectively). Compound 2 has the greatest activity with CC50 ≤ 25 μg/mL and HC50 > 32 μg/mL performed against HEC239 and RBC cell lines. The anti-cancer potential was assessed against the MG-U87 cell line, using cisplatin as the standard (133 µM), indicates 2 displays the greatest activity (IC50: 5.521 µM) at a 5 µM dose. The greatest anti-leishmanial potential was observed for 2 (87.75 at 1000 μg/mL) in comparison to amphotericin B (90.67). The biological assay correlates with the observed maximum of 89% scavenging activity exhibited by 2. The Swiss-ADME data publicised the screened compounds generally follow the rule of 5 of drug-likeness and have good bioavailability potential.
Fulltext Epidemiology and phylogeny of Haemonchus contortus through internal transcribed spacer 2 gene in small ruminants

Ahmad N, Khan SA, Majid HA, Ali R, Ullah R, Bari A, et al.

Front Vet Sci, 2024;11:1380203.
PMID: 38655530 DOI: 10.3389/fvets.2024.1380203

INTRODUCTION: Haemonchus contortus (H. contortus) is a blood-feeding nematode causing infectious disease haemonchosis in small ruminants of tropical and subtropical regions around the world. This study aimed to explore the prevalence and phylogeny of H. contortus in small ruminants using the internal transcribed spacer-2 (ITS-2) gene. In addition, a comprehensive review of the available literature on the status of H. contortus in Pakistan was conducted.
METHODS: Fecal samples were collected from sheep and goats (n = 180). Microscopically positive samples were subjected to DNA extraction followed by PCR using species-specific primers.
RESULTS: The overall prevalence of H. contortus was 25.55% in small ruminants. The prevalence of H. contortus was significantly associated with months and area. The highest occurrence of haemonchosis was documented in July (38.70%), whereas the lowest occurred in December (11.11%), with significant difference. The prevalence was highest in the Ghamkol camp (29.4%) and lowest in the arid zone of the Small Ruminant Research Institute (17.5%) (p = 0.01). The results of the systematic review revealed the highest prevalence of haemonchosis (34.4%) in Khyber Pakhtunkhwa (p = 0.001).
DISCUSSION: Phylogenetic analysis revealed a close relationship between H. contortus and isolates from Asia (China, India, Iran, Bangladesh, Malaysia, and Mongolia) and European countries (Italy and the United Kingdom). It has been concluded that H. contortus is prevalent in small ruminants of Kohat district and all over Pakistan, which could be a potential threat to food-producing animals, farmers, dairy, and the meat industry. Phylogenetic analysis indicates that H. contortus isolates share close phylogenetic relationships with species from Asia and Europe.
Fulltext Engineering of Naproxen Loaded Polymer Hybrid Enteric Microspheres for Modified Release Tablets: Development, Characterization, in silico Modelling and in vivo Evaluation

Hameed HA, Khan S, Shahid M, Ullah R, Bari A, Ali SS, et al.

Drug Des Devel Ther, 2020;14:27-41.
PMID: 32021089 DOI: 10.2147/DDDT.S232111

BACKGROUND: Naproxen (NP) is a non-steroidal anti-inflammatory drug with poor aqueous solubility and low oral bioavailability, which may lead to therapeutic failure. NP causes crucial GIT irritation, bleeding, and peptic and duodenal ulcers.
PURPOSE OF THE STUDY: This study aimed to engineer and characterize polymer hybrid enteric microspheres using an integrated (experimental and molecular modelling) approach with further development to solid dosage form with modified drug release kinetics and improved bioavailability.
MATERIALS AND METHODS: NP loaded polymer hybrid enteric microspheres (PHE-Ms) were fabricated by using a modified solvent evaporation technique coupled with molecular modelling (MM) approach. The PHE-Ms were characterized by particle size, distribution, morphology, crystallinity, EE, drug-polymer compatibility, and DSC. The optimized NP loaded PHE-Ms were further subjected to downstream procedures including tablet dosage form development, stability studies and comparative in vitro-in vivo evaluation.
RESULTS: The hydrophobic polymer EUD-L100 and hydrophilic polymer HPMC-E5 delayed and modified drug release at intestinal pH while imparting retardation of NP release at gastric pH to diminish the gastric side effects. The crystallinity of the NP loaded PHE-Ms was established through DSC and P (XRD). The particle size for the developed formulations of PEH-Ms (M1-M5) was in the range from 29.06 ±7.3-74.31 ± 17.7 μm with Span index values of 0.491-0.69, respectively. The produced NP hybrid microspheres demonstrated retarded drug release at pH 1.2 and improved dissolution at pH 6.8. The in vitro drug release patterns were fitted to various release kinetic models and the best-followed model was the Higuchi model with a release exponent "n" value > 0.5. Stability studies at different storage conditions confirmed stability of the NP loaded PHE-Ms based tablets (P<0.05). The molecular modelling (MM) study resulted in adequate binding energy of co-polymer complex SLS-Eudragit-HPMC-Naproxen (-3.9 kcal/mol). In contrast to the NP (unprocessed) and marketed formulations, a significant increase in the Cmax of PHE-MT1 (44.41±4.43) was observed.
CONCLUSION: The current study concludes that developing NP loaded PHE-Ms based tablets could effectively reduce GIT consequences with restored therapeutic effects. The modified release pattern could improve the dissolution rate and enhancement of oral bioavailability. The MM study strengthens the polymer-drug relationship in microspheres.
Fulltext Multiepitope-Based Subunit Vaccine Design and Evaluation against Respiratory Syncytial Virus Using Reverse Vaccinology Approach

Tahir Ul Qamar M, Shokat Z, Muneer I, Ashfaq UA, Javed H, Anwar F, et al.

Vaccines (Basel), 2020 Jun 08;8(2).
PMID: 32521680 DOI: 10.3390/vaccines8020288

Respiratory syncytial virus (RSV) is primarily associated with respiratory disorders globally. Despite the availability of information, there is still no competitive vaccine available for RSV. Therefore, the present study has been designed to develop a multiepitope-based subunit vaccine (MEV) using a reverse vaccinology approach to curb RSV infections. Briefly, two highly antigenic and conserved proteins of RSV (glycoprotein and fusion protein) were selected and potential epitopes of different categories (B-cell and T-cell) were identified from them. Eminently antigenic and overlapping epitopes, which demonstrated strong associations with their respective human leukocyte antigen (HLA) alleles and depicted collective ~70% coverage of the world's populace, were shortlisted. Finally, 282 amino acids long MEV construct was established by connecting 13 major histocompatibility complex (MHC) class-I with two MHC class-II epitopes with appropriate adjuvant and linkers. Adjuvant and linkers were added to increase the immunogenic stimulation of the MEV. Developed MEV was stable, soluble, non-allergenic, non-toxic, flexible and highly antigenic. Furthermore, molecular docking and molecular dynamics (MD) simulations analyses were carried out. Results have shown a firm and robust binding affinity of MEV with human pathogenic toll-like receptor three (TLR3). The computationally mediated immune response of MEV demonstrated increased interferon-γ production, a significant abundance of immunoglobulin and activation of macrophages which are essential for immune-response against RSV. Moreover, MEV codons were optimized and in silico cloning was performed, to ensure its increased expression. These outcomes proposed that the MEV developed in this study will be a significant candidate against RSV to control and prevent RSV-related disorders if further investigated experimentally.
Fulltext Biogenic Salvia species synthesized silver nanoparticles with catalytic, sensing, antimicrobial, and antioxidant properties

Ihsan S, Gul H, Jamila N, Khan N, Ullah R, Bari A, et al.

Heliyon, 2024 Feb 29;10(4):e25814.
PMID: 38375246 DOI: 10.1016/j.heliyon.2024.e25814

Salvia (Lamiaceae family) is used as a brain tonic to improve cognitive function. The species including S. plebeia and S. moorcroftiana are locally used to cure hepatitis, cough, tumours, hemorrhoids, diarrhoea, common cold, flu, and asthma. To the best of authors' knowledge, no previous study has been conducted on synthesis of S. plebeia and S. moorcroftiana silver nanoparticles (SPAgNPs and SMAgNPs). The study was aimed to synthesize AgNPs from the subject species aqueous and ethanol extracts, and assess catalytic potential in degradation of standard and extracted (from yums, candies, and snacks) dyes, nitrophenols, and antibiotics. The study also aimed at AgNPs as probe in sensing metalloids and heavy metal ions including Pb2+, Cu2+, Fe3+, Ni2+, and Zn2+. From the results, it was found that Salvia aqueous extract afforded stable AgNPs in 1:9 and 1:15 (quantity of aqueous extract and silver nitrate solution concentration) whereas ethanol extract yielded AgNPs in 1:10 (quantity of ethanol extract and silver nitrate solution concentration) reacted in sunlight. The size of SPAgNPs and SMAgNPs determined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were 21.7 nm and 19.9 nm, with spherical, cylindrical, and deep hollow morphology. The synthesized AgNPs demonstrated significant potential as catalyst in dyes; Congo red (85 %), methylene blue (75 %), Rhodamine B (<50 %), nitrophenols; ortho-nitrophenol (95-98 %) and para-nitrophenol (95-98 %), dyes extracted from food samples including yums, candies, and snacks. The antibiotics (amoxicillin, doxycycline, levofloxacin) degraded up to 80 %-95 % degradation. Furthermore, the synthesized AgNPs as probe in sensing of Pb2+, Cu2+, and Fe3+ in Kabul river water, due to agglomeration, caused a significant decrease and bathochromic shift of SPR band (430 nm) when analyzed after 30 min. The Pb2+ ions was comparatively more agglomerated and chelated. Thus, the practical applicability of AgNPs in Pb2+ sensing was significant. Based on the results of this research study, the synthesized AgNPs could provide promising efficiency in wastewater treatment containing organic dyes, antibiotics, and heavy metals.
Fulltext Effective Antiplasmodial and Cytotoxic Activities of Synthesized Zinc Oxide Nanoparticles Using Rhazya stricta Leaf Extract

Najoom S, Fozia F, Ahmad I, Wahab A, Ahmad N, Ullah R, et al.

Evid Based Complement Alternat Med, 2021;2021:5586740.
PMID: 34484393 DOI: 10.1155/2021/5586740

In the present study, zinc oxide (ZnO) nanoparticles were prepared using ZnCl2.2H2O as a precursor, via green route using leaf extract of Rhazya stricta as capping and reducing agent. The prepared ZnO nanoparticles were examined using UV-visible spectrophotometer (UV-Vis), Fourier transform infrared spectrometer (FT-IR), X-ray diffraction spectrometer (XRD), and scanning electron microscope (SEM). The UV-Vis absorption spectrum at 355 nm showed an absorption peak, which indicates the formation of ZnO NPs. The FT-IR spectra analysis was performed to identify the potential biomolecule of the as-prepared ZnO NPs. The FT-IR spectra showed peaks at 3455, 1438, 883, and 671 cm-1 in the region of 4000-500 cm-1, which indicates -OH, NH, C-H, and M-O groups, respectively. The SEM images showed aggregation of ZnO nanoparticles with an average size of 70-90 nm. The XRD study indicated that the ZnO NPs were crystalline in nature with hexagonal wurtzite structure and broad peaks were observed at 2 theta positions 31.8°, 34.44°, 36.29°, 47.57°, 56.61°, 67.96°, and 69.07°. The synthesized ZnO NPs were found to be good antiplasmodial with a 50% inhibitory concentration (IC50) value of 3.41 μg/mL. It is concluded from the current study that the ZnO NPs exhibited noble antiplasmodial activity, and for the improvement of antiplasmodial medications, it might be used after further in vivo studies.
Synthesis of Competitive and Noncompetitive Inhibitors of Alpha-Glucosidase and Anticancer Agents

Ghani U, Syed SA, Aljunidel S, Khan AA, Nur-E-Alam M, AlNoshan A, et al.

Chem Biodivers, 2024 Feb 23.
PMID: 38393939 DOI: 10.1002/cbdv.202301399

Imidazoles and phenylthiazoles are an important class of heterocycles that demonstrate a wide range of biological activities against various types of cancers, diabetes mellitus and pathogenic microorganisms. The heterocyclic structure having oxothiazolidine moiety is an important scaffold present in various drugs, with potential for enzyme inhibition. In an effort to discover new heterocyclic compounds, we synthesized 26 new 4,5-diphenyl-1H-imidazole, phenylthiazole, and oxothiazolidine heterocyclic analogues that demonstrated potent α-glucosidase inhibition and anticancer activities. Majority of the compounds noncompetitively inhibited α-glucosidase except for two that exhibited competitive inhibition of the enzyme. Docking results suggested that the noncompetitive inhibitors bind to an apparent allosteric site on the enzyme located in the vicinity of the active site. Additionally, the analogues also exhibited significant activity against various types of cancers including non-small lung cancer. Since tubulin protein plays an important role in the pathogenesis of non-small lung cancer, molecular docking with one of the target compounds provided important clues to its binding mode. The current work on imidazoles and phenylthiazole derivatives bears importance for designing of new antidiabetic and anticancer drugs.
Fulltext Emerging mechanistic insights of selective autophagy in hepatic diseases

Alim Al-Bari A, Ito Y, Thomes PG, Menon MB, García-Macia M, Fadel R, et al.

Front Pharmacol, 2023;14:1149809.
PMID: 37007026 DOI: 10.3389/fphar.2023.1149809

Macroautophagy (hereafter referred to as autophagy), a highly conserved metabolic process, regulates cellular homeostasis by degrading dysfunctional cytosolic constituents and invading pathogens via the lysosomal system. In addition, autophagy selectively recycles specific organelles such as damaged mitochondria (via mitophagy), and lipid droplets (LDs; via lipophagy) or eliminates specialized intracellular pathogenic microorganisms such as hepatitis B virus (HBV) and coronaviruses (via virophagy). Selective autophagy, particularly mitophagy, plays a key role in the preservation of healthy liver physiology, and its dysfunction is connected to the pathogenesis of a wide variety of liver diseases. For example, lipophagy has emerged as a defensive mechanism against chronic liver diseases. There is a prominent role for mitophagy and lipophagy in hepatic pathologies including non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and drug-induced liver injury. Moreover, these selective autophagy pathways including virophagy are being investigated in the context of viral hepatitis and, more recently, the coronavirus disease 2019 (COVID-19)-associated hepatic pathologies. The interplay between diverse types of selective autophagy and its impact on liver diseases is briefly addressed. Thus, modulating selective autophagy (e.g., mitophagy) would seem to be effective in improving liver diseases. Considering the prominence of selective autophagy in liver physiology, this review summarizes the current understanding of the molecular mechanisms and functions of selective autophagy (mainly mitophagy and lipophagy) in liver physiology and pathophysiology. This may help in finding therapeutic interventions targeting hepatic diseases via manipulation of selective autophagy.