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The use of protease inhibitors in human immunodeficiency virus type 1 (HIV-1) treatment is limited by adverse effects, including metabolic complications. To address these challenges, efforts are underway in the pursuit of more potent and less toxic HIV-1 protease inhibitors. Repurposing existing drugs offers a promising avenue to expedite the drug discovery process, saving both time and costs compared to conventional de novo drug development. This study screened FDA-approved and investigational drugs in the DrugBank database for their potential as HIV-1 protease inhibitors. Molecular docking studies and cell-based assays, including anti-HIV-1 in vitro assays and XTT cell viability tests, were conducted to evaluate their efficacy. The study findings revealed that CBR003PS, an antibiotic currently in clinical use, and CBR013PS, an investigational drug for treating endometriosis and uterine fibroids, exhibited significant binding affinity to the HIV-1 protease with high stability. Their EC50 values, measured at 100% cell viability, were 9.4 nM and 36.6 nM, respectively. Furthermore, cell-based assays demonstrated that these two compounds showed promising results, with therapeutic indexes higher than 32. In summary, based on their favorable therapeutic indexes, CBR003PS and CBR013PS show potential for repurposing as HIV-1 protease inhibitors. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus type 1 (HIV-1) has continued to be a global concern. With the new HIV incidence, the emergence of multi-drug resistance and the untoward side effects of currently used anti-HIV drugs, there is an urgent need to discover more efficient anti-HIV drugs. Modern computational tools have played vital roles in facilitating the drug discovery process. This research focuses on a pharmacophore-based similarity search to screen 111,566,735 unique compounds in the PubChem database to discover novel HIV-1 protease inhibitors (PIs). We used an in silico approach involving a 3D-similarity search, physicochemical and ADMET evaluations, HIV protease-inhibitor prediction (IC50/percent inhibition), rigid receptor–molecular docking studies, binding free energy calculations and molecular dynamics (MD) simulations. The 10 FDA-approved HIV PIs (saquinavir, lopinavir, ritonavir, amprenavir, fosamprenavir, atazanavir, nelfinavir, darunavir, tipranavir and indinavir) were used as reference. The in silico analysis revealed that fourteen out of the twenty-eight selected optimized hit molecules were within the acceptable range of all the parameters investigated. The hit molecules demonstrated significant binding affinity to the HIV protease (PR) when compared to the reference drugs. The important amino acid residues involved in hydrogen bonding and п-п stacked interactions include ASP25, GLY27, ASP29, ASP30 and ILE50. These interactions help to stabilize the optimized hit molecules in the active binding site of the HIV-1 PR (PDB ID: 2Q5K). HPS/002 and HPS/004 have been found to be most promising in terms of IC50/percent inhibition (90.15%) of HIV-1 PR, in addition to their drug metabolism and safety profile. These hit candidates should be investigated further as possible HIV-1 PIs with improved efficacy and low toxicity through in vitro experiments and clinical trial investigations. [ABSTRACT FROM AUTHOR]

The drugs used for treating bone diseases (BDs), at present, elicit hazardous side effects that include certain types of cancers and strokes, hence the ongoing quest for the discovery of alternatives with little or no side effects. Natural products (NPs), mainly of plant origin, have shown compelling promise in the treatments of BDs, with little or no side effects. However, the paucity in knowledge of the mechanisms behind their activities on bone remodeling has remained a hindrance to NPs' adoption. This review discusses the pathological development of some BDs, the NP-targeted components, and the actions exerted on bone remodeling signaling pathways (e.g., Receptor Activator of Nuclear Factor κ B-ligand (RANKL)/monocyte/macrophage colony-stimulating factor (M-CSF)/osteoprotegerin (OPG), mitogen-activated protein kinase (MAPK)s/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Kelch-like ECH-associated protein 1 (Keap-1)/nuclear factor erythroid 2–related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1), Bone Morphogenetic Protein 2 (BMP2)-Wnt/β-catenin, PhosphatidylInositol 3-Kinase (PI3K)/protein kinase B (Akt)/Glycogen Synthase Kinase 3 Beta (GSK3β), and other signaling pathways). Although majority of the studies on the osteoprotective properties of NPs against BDs were conducted ex vivo and mostly on animals, the use of NPs for treating human BDs and the prospects for future development remain promising. [ABSTRACT FROM AUTHOR]

Twelve new derivatives of benzothiazole bearing benzenesulphonamide and carboxamide were synthesised and investigated for their in vivo anti-inflammatory, analgesic and ulcerogenic activities. Molecular docking showed an excellent binding interaction of the synthesised compounds with the receptors, with 17c showing the highest binding energy (-12.50 kcal/mol). Compounds 17c and 17i inhibited carrageenan-induced rat paw oedema at 72, 76, and 80% and 64, 73, and 78% at 1 h, 2 h, and 3 h, respectively. In the analgesic activity experiment, compounds 17c, 17 g, and 17i had ED50 (µM/kg) of 96, 127, and 84 after 0.5 h; 102, 134, and 72 after 1 h and 89, 156, and 69 µM/kg after 2 h, respectively, which were comparable with 156, 72, and 70 µM/kg for celecoxib. The ulcerogenic index of the most active derivatives 17c and 17i were 0.82 and 0.89, respectively, comparable to 0.92 for celecoxib. The physicochemical studies of the new derivatives showed that they will not have oral bioavailability problems. [ABSTRACT FROM AUTHOR]

Some derivatives of phenothiazine and phenoxazine compounds were synthesized via Hiyama‐cross coupling reaction protocol. The intermediates were prepared by reacting 2‐aminothiophenol, 2‐aminopyridin‐3‐ol and 4,5‐diamino‐6‐hydroxylpyrimidin‐2‐thiol with 2,3‐dibromonaphthalene‐1,4‐dione in alkaline medium of anhydrous sodium carbonate. These intermediates were subjected to the fluoride‐free Hiyama cross‐coupling reaction with 2‐(dimethylsilyl)pyridine and dimethyl(2‐thienyl)silanol using magnetically separable Pd/Fe3O4 as the catalyst under aqueous conditions to yield the derivatives. Molecular descriptors of these compounds were evaluated for their drug‐likeness. Pharmacokinetic parameters were also evaluated. Molecular docking studies were performed. The synthesized compounds showed drug‐likeness. Pharmacokinetic evaluation reveals a strong plasma protein binding and potentials to cross blood‐brain barrier. 6‐(Thiophen‐2‐yl)‐5H‐11‐azabenzo[a]phenoxazin‐5‐one (8 b) and 11‐Amino‐9‐thio‐6‐(thiophen‐2‐yl)‐5H‐8,11‐diazabenzo[a]phenoxazin‐5‐one (9 b) showed highest binding energies of −5.74 and −7.25 kcal/mol with the protein targets glucosamine‐6‐phosphate synthase (2VF5) and lanosterol‐14α‐demethylase (3JUV) respectively. The phenoxazines synthesized were found to be potential inhibitors of glucosamine‐6‐phosphate synthase and lanosterol‐14α‐demethylase. [ABSTRACT FROM AUTHOR]

Two novel heterocyclic ligands, 2‐[(5‐fluoro‐1,3‐benzothiazol‐2‐yl)amino]naphthalene‐1,4‐dione (HL1) and 2‐[(5‐methyl‐1,3‐benzothiazol‐2‐yl)amino]naphthalene‐1,4‐dione (HL2), and their Pd(II), Ni(II) and Co(II) complexes were prepared and characterized using 1H NMR, 13C NMR, infrared and UV–visible spectroscopic techniques, elemental analysis, magnetic susceptibility, thermogravimetry and molar conductance measurements. The infrared spectral data showed that the chelation behaviours of the ligands towards the transition metal ions were through one of the carbonyl oxygen and deprotonated nitrogen atom of the secondary amine group. Molar conductance results confirmed that the complexes are non‐electrolytes in dimethylsulfoxide. The geometries of the complexes were deduced from magnetic susceptibility and UV–visible spectroscopic results. Second‐order perturbation analysis using density functional theory calculation revealed a stronger intermolecular charge transfer between ligand and metal ion in [NiL1(H2O)2(CH3COO‐)] and CoL1 compared to the other complexes. The in vitro antibacterial activity of the compounds against some clinically isolated bacteria strains showed varied activities. [NiL1(H2O)2(CH3COO‐)] exhibited the best antibacterial results with a minimum inhibitory concentration of 50 μg mL−1. The molecular interactions of the compounds with various drug targets of some bacterial organisms were established in a bid to predict the possible mode of antibacterial action of the compounds. The ferrous ion chelating ability of the ligands indicated that HL1 is a better Fe2+ ion chelator, with an IC50 of 29.79 μg mL−1, compared to HL2 which had an IC50 of 98.26 μg mL−1. [ABSTRACT FROM AUTHOR]

Background: The leaves of Stachytarpheta cayennensis C. Rich. (Verbenaceae) have been reported to possess potent anti-inflammatory and anti-malarial activities. Due to close association between inflammatory and immune responses, we evaluated the immunomodulatory activity of leaves extract of S. cayennensis. The combined effects of the leaves extract and artesunate, a standard antimalarial agent with immunomodulatory effects, were also evaluated. Methods: The immunomodulatory activity of the methanol extract of the leaves of S. cayennensis (MESC) was evaluated in mice using the Delayed-Type hypersensitivity response (DTHR), primary and secondary humoral immune responses and the in vivo leucocyte mobilization tests. The immunomodulatory effect of artesunate and the combined effects of MESC and artesunate were evaluated using the phagocytic activity of polymorphonuclear neutrophils. Acute toxicity and lethality test in addition to the preliminary phytochemical studies of MESC were also performed. Results: The MESC exhibited 64.21% inhibition of DTHR at 500 mg/kg dose and evoked 139.64% of phagocytic stimulation at 100 µg/ml dose. Also MESC significantly (p < 0.05) showed dose related stimulation of humoral immunity and a highest percentage leucocyte mobilization of 10.15% at 250 mg/kg dose. Artesunate offered a non-significant (p > 0.05) percentage phagocytic stimulation (PPS) while the combined effect of artesunate and MESC exhibited a significant (p < 0.05) dose dependent PPS with highest PPS of 393.77% at 100 µg/ml. The LD50 of the MESC was estimated to be greater than 5000 mg/kg since there were no lethality and signs of acute intoxication after 48 h observation. Preliminary phytochemical analysis revealed the presence of carbohydrates, glycosides, flavonoids, saponins, alkaloids, terpenoids and steroids. Conclusions: The results of this study indicated that MESC possesses immunostimulatory action with significant synergistic effects with artesunate, and can therefore, offer immune boosting activities in disorders of immune suppression. [ABSTRACT FROM AUTHOR]

Purpose: To formulate Cannabis sativa-based syrup and investigate its anti-inflammatory potential and the stability of the formulation under stress conditions. Methods: The syrup was prepared using different combinations of crude C. sativa resin, propylene glycol, aspartame, sucrose, sodium metabisulphite (SMBs) and ethylenediaminetetraacetic acid (EDTA). The stability of the formulations was determined under accelerated temperature conditions. The anti-inflammatory activity of the resin and different formulations were evaluated by the egg albumin induced paw edema model in rats. Biochemical assay was determined by Reitman and Frankel colorimetric assay method while hematological assay was evaluated by standard protocols. Results: EDTA-containing syrup (CE) was the most stable with estimated shelf-life of 2204 days (K25ºC, 4.78 x 10-5/day). Higher propylene glycol levels significantly improved anti-inflammatory activity compared to those containing a lower amount. All the formulations showed anti-inflammatory activity higher than the crude resin with a dose-dependent inhibition of paw edema compared with the control. There was no significant difference (p < 0.05) between the serum glutamate-oxaloacetate transaminase (SGOT, 13.821 ± 0.190 - 16.008 ± 1.012), serum glutamate-pyruvate transaminase (SGPT, 19.241 ± 1.027 - 22.901 ± 1.093) and urea (9.812 ± 0.252 - 10.054 ± 0.252) levels of the treated and 16.856 ± 1.053, 24.960 ± 0.101 and 10.654 ± 0.925 units/L of the control animals respectively. With the exception of eosinophil that disappeared from the blood in the third week, all the hematological parameters showed a gradual increase in lymphocytes, neutrophils, monocytes, packed cell volume (PCV), white and red blood cell counts in the third week compared to control. Conclusion: Formulation of C. sativa as syrup using efficient carriers improves the pharmacological activity of the crude extract. SMBs and EDTA significantly enhance the stability of the syrup with no observable biochemical and hematological changes in treated animals [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the in vitro anti-oxidant and anti-inflammatory potential of the most potent and abundant metabolite, 3-methoxy quercetin (3-MQ), from extract fractions of mistletoe, Loranthus micranthus Linn (Loranthaceae) parasitic on Kola acuminata Schott & Endl, (Malvaceae), also known as Garcinia kola Heckel, (Clusiaceae). Methods: Compounds isolated through a combination of chromatographic techniques were screened for in vitro antioxidant potential using the diphenyl picrazyl hydrazine (DPPH) radical-based model. Cell viability at 1-1000 μM 3-MQ in 24 h was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test. Lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (n = 5) five (5) replicates. Results: Ten (10) known compounds including 3-MQ (1) were isolated and characterized. 3-MQ exhibited highly significant (p < 0.05) antioxidant activity with 50 % inhibitory concentration (IC50) of 15.0 μM; concentrations ≤100 μM did not exert cytotoxic effect. 3-MQ, at 25 and 125 μM concentrations, significantly (p < 0.05) inhibited the production of TNF-a by 82 and 100 %, respectively, compared to controls. Conclusion: The results demonstrate the potent anti-inflammatory activity of 3-MQ and suggests its use as a potential alternative therapy for inflammation and related diseases. [ABSTRACT FROM AUTHOR]

• Inflammatory disease are prevalent worldwide and can be life threatening. • The need to develop newer anti-inflammatory agents is eminent. • Carboxamides and sulphonamides are antioxidant, antimicrobial anti-inflammatory agents. • The novel compounds are good antioxidant, antimicrobial and anti-inflammatory agents. Ten new derivatives of benzenesulphonamide bearing carboxamide functionality were synthesized and investigated for their in vitro antimicrobial, antioxidant and in vivo anti-inflammatory activities. Compound 9d inhibited carrageenan induced rat-paw oedema at 93.81, 88.79 and 86.09% at 1 h, 2 h and 3 h administration respectively. In the antimicrobial activity, compound 9a (6.54, 6.69 and 6.64 mg/mL) was most potent against S. aureus , B. subtilis and C. albicans respectively, compound 9e (6.45 and 6.46 mg/mL) was most active against P. aeruginosa and A. niger respectively while compound 9i (6.24 mg/mL) was most active against E. coli. Only compound 9a (IC 50 0.3052 mg/mL) had comparable activity with Vitamin C (IC 50 0.2090 mg/mL) in the antioxidant assay. [ABSTRACT FROM AUTHOR]