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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]

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]

• Pyrimidine Schiff bases are platelet aggregation inhibitors. • The synthesized complexes adopted varied geometries based on data obtained. • The compounds had enhanced radical scavenging potentials from antioxidant studies. • Cu-L2 had the highest binding affinity with 1WS3 from the fungus Aspergillus flevush. The amino-pyrimidine-based imine-chelators, 1-((pyrimidin-2-ylimino)methyl)naphthalene-2-ol(HL1), 2-(((2-hydroxynaphthalen-1-yl)methylene)amino)pyrimidine-4,6-diol(HL2) and 1-(((4,6-dimethylpyrimidin-2-yl)imino)methyl)naphthalen-2-ol(HL3) have been synthesized by facile reaction of 2‑hydroxyl-1-naphthaldehyde with 2-aminopyrimidine, 2-amino-4,6-dihydroxypyrimidine, and 2-amno-4,6-dimethypyrimidine respectively. The chelators were coordinated with Fe(II) sulfate and Cu(II) acetate to afford the corresponding complexes which were fully characterized. The Cu(II) complex exhibited superlative antimicrobial activity with an inhibitory growth zone reaching 26.5 mm outperforming both the chelators and the Fe(II) complexes. Thus Cu(II) complex has potential significance in new antibacterial drug designs and isolation. The impressive activity was due chelation which increased the lipophilic feature of the Cu(II) complex, thereby favouring its infiltration through the lipid layers of the bacterial membranes. However, compared to other samples, Fe-L2 has the best antifungal performance activity against Aspergillus niger, Aspergillus flevus, and Rhizopus stolonifer with inhibition zone of 29±1.4, 19±2.1 and 22±1 respectively. The C 18 H 12 N 5 O 6 antioxidant result confirmed that Cu-L2 had the highest scavenging ability (99.80%) at 200 μg/mL. Interestingly, Cu-L2 exhibited the highest antioxidant actions both in vitro and in silco evaluations, hence can serve as a potential antioxidant agent. Molecular docking determinations displayed a substantial binding affinity with the drug targets suggesting that the metallic compounds could be exploited for drugs design. [Display omitted] [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]

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]

We report the synthesis and characterization of some organotin(IV) compounds of N -butyl- N -phenyldithiocarbamate complexes represented as [C 4 H 9 SnL 2 ] (1) , (CH 3) 2 SnL 2 ] (2) , (C 4 H 9) 2 SnL 2 ] (3) , (C 6 H 5) 2 SnL 2 ] (4) ], where L is N -butyl- N -phenyldithiocarbamate. Single crystal X-ray analysis of compounds 2 and 3 showed that they possess five or six coordinate geometry. These compounds were evaluated for their antimicrobial properties against Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Bacillus cereus, Staphylococcus aureus, Candida albicans and Aspergillus flavus, and in-vitro cytotoxic activities against human cervical carcinoma (HeLa) cells. The antimicrobial studies of the complexes revealed that diaryl substituted organotin(IV) dithiocarbamate complex (4) had the best antimicrobial activity compared to the other complexes. The antimicrobial potency were in the order 2 ˂ 3 ˂ 1 ˂ 4. The IC 50 results obtained for the cytotoxic activity showed that the mono-alkyl substituted organotin(IV) dithiocarbamate (1) displayed the least IC 50 value. This high activity was due to its selectivity towards the HeLa cell line, compared to the other compounds and the standard drug, 5-fluorouracil (5-FU). Furthermore, compounds 3 and 4 also gave lower IC 50 values than 5-FU which resulted in better cytotoxicity towards the HeLa cell line. Molecular docking study was used to explore the interactions of the compounds with several drug targets. The compounds showed high binding affinity with the drug targets and agrees well with the antimicrobial study. Image 1 • Organotin(IV) dtc complexes were derived from of N -butyl- N -phenylamine. • Complexes showed promising biological actions in silico and in vitro. • Molecular docking agrees with the antimicrobial study. [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]

A pyrimidine-based ligand, 2-(pyrimidin-2-ylamino)naphthalene-1,4-dione (L), has been synthesized by the reaction of 2-aminopyrimidine with 2-hydroxy-1,4-napthoquinone. Reaction of the ligand with Ni(II), Co(II), Mn(II) and Zn(II) acetate gave the corresponding metal complexes which were characterized by spectroscopic techniques, (infrared, electronic), elemental analysis, room-temperature magnetometry, conductance measurements and thermogravimetry-differential scanning calorimetry (TG-DSC) analyses. The room-temperature magnetic data and electronic spectral measurements of the complexes gave evidence of 4-coordinate square planar/tetrahedral geometry. The thermal analyses values obtained indicated the monohydrate complexes. The antimicrobial screening of the compounds showed mild to very good results. The Mn(II) complex showed the best result within in the range of 11.5–29 mm. The electronic, structural and spectroscopic properties of the complexes were further discussed using density functional theory. Molecular docking studies showed significant binding affinity with the drug targets and the metal complexes have potentials to be used as drugs. [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]

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]

• Synthesis of a potassium salt of N,N-bis(3,3-dimethyl-allyl)-dithiocarbamate and its Ni(II), Pt(II) and Pd(II) complexes. • Single crystal X-ray diffraction studies for Pt (II) and Pd(II) complexes and magnetic susceptibility measure for the Ni(II) complex were done. • Antimicrobial susceptibility screening of the compounds was carried out using Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and C. albicans. • Molecular docking studies of the ligand and its coordination compounds with some enzymes responsible for the survival of these microbes were carried out. A potassium salt of N,N-bis(3,3-dimethyl-allyl)-dithiocarbamate has been synthesized from three step processes involving the synthesis of bis(3,3-dimethyl-allyl)-cyanamide and subsequent conversion to N,N-bis(3,3-dimethyl-allyl)amine. The dithiocarbamate ligand was obtained in a rapid exothermic reaction involving the amine and carbon disulfide in alkali medium, and its Ni(II), Pt(II) and Pd(II) complexes are reported. The characterization of the ligand and its metal complexes were carried out using various spectroscopic (FTIR, NMR, Mass) and magnetic susceptibility measurements. Square planar structures were proposed for the complexes as obtained from single crystal X-ray diffraction studies for Pt (II) and Pd(II) complexes and magnetic moment study for the Ni(II) complex. Antimicrobial susceptibility screening of the compounds was carried out using Gram positive strains: Bacillus subtilis and Staphylococcus aureus , Gram negative strains: Escherichia coli and Pseudomonas aeruginosa , and a fungal species: C. albicans. The drugs ciprofloxacin and ketoconazole were used as the reference standard drugs. The metal complexes showed significant antimicrobial activity. Thus, further study on this approach could pave a way for the development of dithiocarbamate-metal complex based antimicrobial agents. [Display omitted] [ABSTRACT FROM AUTHOR]

• In the tropical regions of the world, protozoan parasites cause severe diseases. • Malaria and human african trypanosomaisis (HAT) stand in forefront. • There are problems of parasite resistance to drugs and current inadequate chemotherapy for these diseases. • Result of this research shows interesting antimalaria and antitrypanosomaisis activities. • Molecular docking result showed good interaction between the compounds and proteins. The increasing emergence of malaria drug-resistant parasites and the deficiency in effective chemotherapy for trypanosomiasis represents a huge challenge in infectious disease treatment in tropical regions. As regards to developing effective antiprotozoal agents, ten new ile-gly dipeptide sulphonamide derivatives were synthesized by condensing compound (10) with (8a-j) using peptide coupling reagents. Compounds 11b, 11i and 11j were most potent in clearing Trypanosome brucei in mice with 11b showing comparable activity with diminazene aceturate. In the antimalarial study, 11b was the most active compound, even better than the standard. Molecular docking result suggests good interaction between the reported compounds and the target protein. The results of haematological analysis, liver and kidney function tests showed that the compounds had no adverse effect on the blood and organs. Compound 11b stands out amongst the derivatives haven shown better activity in both the antimalarial and antitrypanosomal assay. [ABSTRACT FROM AUTHOR]

Two asymmetrically substituted ureas N,N ́ -(2-carboxylphenyl)phenyl urea (L 1) and diethyl 4-(3-phenylureido)benzylphosphonate (L 2) were synthesized and characterized by spectroscopic and X-ray crystallographic analysis. The two compounds crystallized in the centrosymmetric monoclinic crystal system and P2 1 /n space group. The carboxyl substituted urea L 1 crystallized with one molecule in the asymmetric unit. A hydrogen-bonded dimer is formed between the carboxyl group of the urea and a second molecule of the compound. The urea functional group is involved in both intramolecular and intermolecular hydrogen bonding with the carboxyl and carbonyl oxygens, respectively. The interplay of intermolecular and intramolecular hydrogen bonding in the compound results in a 2-D hydrogen-bonded structure. The phosphoryl-substituted urea L 2 , on the other hand, crystallized with two molecules in the asymmetric unit, resulting in a hydrogen-bonded tetramer in the crystal lattice. Non-covalent interactions (NCI) analysis of the two compounds revealed the presence of competitive interactions between the urea functional group and the carboxyl and phosphoryl substituents in L 1 and L 2 , respectively. Molecular docking calculations predicted favorable binding interactions between the ureas and the two anticancer protein targets EGFR kinase (2J5F) and anaplastic lymphoma kinase (5J7H). Image 1 • Two asymmetrically substituted ureas were synthesized and structurally characterized. • Noncovalent interaction analysis revealed competitive hydrogen bonding interactions. • Docking studies showed favorable binding between ureas and anticancer protein targets. [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]

Background: The use of statin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for the treatment of dyslipidemia has been associated with dose limiting hepatoxicity, mytotoxicity and tolerability due to myalgias thereby necessitating the synthesis of new drug candidates for the treatment of lipid disorder. Methods: The reaction of appropriate benzenesulphonamide with substituted phenoxazinone in the presence of phenylboronic acid gave the targeted compounds. The molecular docking study were carried out using autodock tool against peroxisome proliferator activated receptor alpha. The in vivo lipid profile were assayed using conventional methods. The kidney and liver function test were carried out to assess the effect of the derivatives on the organs. The LD50 of the most active derivatives were determined using mice. Results: The targeted compounds were successfully synthesized in excellent yields and characterized using spectroscopic techniques. The results of the molecular docking experiment showed that they were good stimulant of peroxisome proliferator activated receptor alpha. Compound 9f showed activity at Ki of 2.8 nM and binding energy of 12.6 kcal/mol. All the compounds tested reduced triglyceride, total cholesterol, low density lipoprotein cholesterol and very low density lipoprotein cholesterol level in the mice model. Some of the reported compounds also increased high density lipoprotein cholesterol level in the mice. The compounds did not have appreciable effect on the kidney and liver of the mice used. The LD50 showed that the novel compounds have improved toxicity profile. Conclusion: The synthesis of fifteen new derivatives of carboxamides bearing phenoxazinone and sulphonamide were successful. The compounds possessed comparable activity to gemfibrozil. The reported compounds had better toxicity profile than gemfibrozil and could serve as a replacement for the statins and fibrate class of lipid agents. [ABSTRACT FROM AUTHOR]