Medicinal chemistry perspectives on the development of piperazine-containing HIV-1 inhibitors.

The Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS), one of the most perilous diseases known to humankind. A 2023 estimate put the number of people living with HIV around 40 million worldwide, with the majority benefiting from various antiretroviral therapies. Consequently, the urgent need for the development of effective drugs to combat this virus cannot be overstated. In the realm of medicinal and organic chemistry, the synthesis and identification of novel compounds capable of inhibiting HIV enzymes at different stages of their life cycle are of paramount importance. Notably, the spotlight is on the progress made in enhancing the potency of HIV inhibitors through the use of piperazine-based compounds. Multiple studies have revealed that the incorporation of a piperazine moiety results in a noteworthy enhancement of anti-HIV activity. The piperazine ring assumes a pivotal role in shaping the pharmacophore responsible for inhibiting HIV-1 at critical stage, including attachment, reverse transcription, integration, and protease activity. This review also sheds light on the various opportunities that can be exploited to develop effective antiretroviral targets and eliminate latent HIV reservoirs. The advancement of highly potent analogues in HIV inhibitor research has been greatly facilitated by contemporary medicinal strategies, including molecular/fragment hybridization, structure-based drug design, and bioisosterism. These techniques have opened up new avenues for the development of compounds with enhanced efficacy in combating the virus.

Substituent and solvent effects on UV-visible absorption spectra of chalcones derivatives: Experimental and computational studies.

The electronic spectra of the title compounds were measured in ethanol and cyclohexane. Three band systems are distinguished in the spectra of which the first and second band systems are attributed to local excitation of PhCH and PhCO rings. The third absorption band is assigned to a charge transfer (CT) band and is associated with the CO-CH=CH moiety. The solvent plays an important role in the absorption spectra and causes the CT band to consist of two electronic transitions. The effect of substituents on the phenyl rings on the charge transfer band of chalcone derivatives was also established in the two solvents. The converged gas-phase geometries of the studied chalcones was optimized using the DFT PBE0 functional with the basis set 6-311++G**. DFT calculations has been performed for an ethanol solution (using TD-PBE0/6-311++G**) level to understand electronic transitions on terms of energies and oscillator strengths to study the substituent effect on the electronic transitions of the chalcone derivatives. To consider the solvation effect of ethanol on the absorptions, the integral equation formalism variant of the polarizable continuum model (IEFPCM) was used. The calculated energies were in good agreement with experiment results. The molecular modelling technique was followed to monitor the effect of substitutions on the HOMO/LUMO energy and total dipole moment. Transitions between natural transition orbitals are also described as part of this study.

Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines.

BACKGROUND: Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. MATERIAL AND METHODS: Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC50 values and binding energies. RESULTS: The compounds displayed IC50 values between 0.7±0.03 and 20.2±0.25µM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from -9.00±0.10 to -6.20±0.02kcal/mol and pKi values from 0.24±0.04 to 29.17±0.88µM. At the ATP-binding site of P-gp, lowest binding energies ranged from -9.78±0.17 to -6.79±0.01kcal/mol and pKi values from 0.07±0.02 to 0.03±0.03µM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF-CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R=0.797 and R=0.794 for training and test sets). CONCLUSION: Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR.

A new vanadium (III) complex of 2,6-bis(3,5-diphenylpyrazol-1-ylmethyl)pyridine as a catalyst for ethylene polymerization.

The tridentate ligand 2,6-bis(3,5-diphenylpyrazol-1-ylmethyl)pyridine, abbreviated as 2,6-[(3,5-ph2pz-CH2)2-py], a new pyridine-pyrazole derivative, was prepared from 2,6-bis(bromomethyl)pyridine and 3,5-diphenylpyrazole. The ligand was characterized by means of elemental analyses, ATR-IR, ¹H- and ¹³C-NMR spectroscopy and single crystal X-ray crystallography. Using this ligand, a new mononuclear vanadium (III) complex, {2,6-[(3,5-ph2pz)CH2]2py}VCl3 was prepared and characterized by elemental analysis, ATR-IR and HR-MS. The complex was investigated as a catalyst for ethylene polymerization and compared with 2,6-[(3,5-Me2pz)CH2]2py}VCl3 to explore the effect of the substituent on the pyrazolyl rings on ethylene polymerization. High catalytic activity was observed at ambient temperature. After treatment with AlEtCl2, these complexes showed high activity for ethylene polymerization converting ethylene to highly linear polyethylene and affording high molecular weight polymers (up to 1.0 × 106 g/mol) with unimodal molecular weight distributions.

Oxidation of benzoin catalyzed by oxovanadium(IV) schiff base complexes.

BACKGROUND: The oxidative transformation of benzoin to benzil has been accomplished by the use of a wide variety of reagents or catalysts and different reaction procedures. The conventional oxidizing agents yielded mainly benzaldehyde or/and benzoic acid and only a trace amount of benzil. The limits of practical utilization of these reagents involves the use of stoichiometric amounts of corrosive acids or toxic metallic reagents, which in turn produce undesirable waste materials and required high reaction temperatures.In recent years, vanadium complexes have attracted much attention for their potential utility as catalysts for various types of reactions. RESULTS: Active and selective catalytic systems of new unsymmetrical oxovanadium(IV) Schiff base complexes for the oxidation of benzoin is reported. The Schiff base ligands are derived between 2-aminoethanol and 2-hydroxy-1-naphthaldehyde (H2L1) or 3-ethoxy salicylaldehyde (H2L3); and 2-aminophenol and 3-ethoxysalicylaldehyde (H2L2) or 2-hydroxy-1-naphthaldehyde (H2L4). The unsymmetrical Schiff bases behave as tridentate dibasic ONO donor ligands. Reaction of these Schiff base ligands with oxovanadyl sulphate afforded the mononuclear oxovanadium(IV) complexes (VIVOLx.H2O), which are characterized by various physico-chemical techniques.The catalytic oxidation activities of these complexes for benzoin were evaluated using H2O2 as an oxidant. The best reaction conditions are obtained by considering the effect of solvent, reaction time and temperature. Under the optimized reaction conditions, VOL4 catalyst showed high conversion (>99%) with excellent selectivity to benzil (~100%) in a shorter reaction time compared to the other catalysts considered. CONCLUSION: Four tridentate ONO type Schiff base ligands were synthesized. Complexation of these ligands with vanadyl(IV) sulphate leads to the formation of new oxovanadium(IV) complexes of type VIVOL.H2O.Elemental analyses and spectral data of the free ligands and their oxovanadium(IV) complexes were found to be in good agreement with their structures, indicating high purity of all the compounds.Oxovanadium complexes were screened for the oxidation of benzoin to benzil using H2O2 as oxidant. The effect of time, solvent and temperature were optimized to obtain maximum yield. The catalytic activity results demonstrate that these catalytic systems are both highly active and selective for the oxidation of benzoin under mild reaction conditions.

A reactivity-selectivity study of the Friedel-Crafts acetylation of 3,3'-dimethylbiphenyl and the oxidation of the acetyl derivatives.

BACKGROUND: Friedel-Crafts acetylation is an important route to aromatic ketones, in research laboratories and in industry. The acetyl derivatives of 3,3'-dimethylbiphenyl (3,3'-dmbp) have applications in the field of liquid crystals and polymers and may be oxidized to the dicarboxylic acids and derivatives that are of interest in cancer treatment. FINDINGS: The effect of solvent and temperature on the selectivity of monoacetylation of 3,3'-dmbp by the Perrier addition procedure was studied using stoichiometric amounts of reagents. 4-Ac-3,3'-dmbp was formed almost quantitatively in boiling 1,2-dichloroethane and this is almost twice the yield hitherto reported. Using instead a molar ratio of substrate:AcCl:AlCl3 equal to 1:4:4 or 1:6:6 in boiling 1,2-dichloroethane, acetylation afforded 4,4'- and 4,6'-diacetyl-3,3'-dmbp in a total yield close to 100%. The acetyl derivatives were subsequently converted to the carboxylic acids by hypochlorite oxidation. The relative stabilities of the isomeric products and the corresponding σ-complexes were studied by DFT calculations and the data indicated that mono- and diacetylation followed different mechanisms. CONCLUSIONS: Friedel-Crafts acetylation of 3,3'-dmbp using the Perrier addition procedure in boiling 1,2-dichloroethane was found to be superior to other recipes. The discrimination against the 6-acetyl derivative during monoacetylation seems to reflect a mechanism including an AcCl:AlCl3 complex or larger agglomerates as the electrophile, whereas the less selective diacetylations of the deactivated 4-Ac-3,3'-dmbp are suggested to include the acetyl cation as the electrophile. The DFT data also showed that complexation of intermediates and products with AlCl3 does not seem to be important in determining the mechanism.