Experimental Examination of Solubility and Lipophilicity as Pharmaceutically Relevant Points of Novel Bioactive Hybrid Compounds

Abstract

The important physicochemical properties of three novel bioactive hybrid compounds with different groups (-CH3, -F and -Cl) were studied, including kinetic and thermodynamic solubility in pharmaceutically relevant solvents (buffer solutions and 1-octanol) as well as partition coefficient in system 1-octanol/buffer pH 7.4. The aqueous solubility of these chemicals is poor and ranged from 0.67 × 10−4 to 1.98 × 10−3 mol·L−1. The compounds studied are more soluble in the buffer pH 2.0, simulating the gastrointestinal tract environment (by an order of magnitude) than in the buffer pH 7.4 modelling plasma of blood. The solubility in 1-octanol is significantly higher; that is because of the specific interactions of the compounds with the solvent. The prediction solubility behaviour of the hybrid compounds using Hansen’s three-parameter approach showed acceptable results. The experimental solubility of potential drugs was successfully correlated by means of two commonly known equations: modified Apelblat and van’t Hoff. The temperature dependencies of partition coefficients of new hybrids in the model system 1-octanol/buffer pH 7.4 as a surrogate lipophilicity were measured by the shake flask method. It was found that compounds demonstrated a lipophilic nature and have optimal values of partition coefficients for oral absorption. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than fluconazole. In addition, the thermodynamic aspects of dissolution and partition processes have been examined. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than the reference drug.

Halogenated Antimicrobial Agents to Combat Drug-Resistant Pathogens

“…Similarly, fluconazole was hybridized with a halogenated phenyl urea group to overcome resistant C. albicans, and in a similar study, halogenated thiazolo[4,5-d]pyrimidine was employed (Fig. 21C-D) (Shafiei et al, 2021;Sharapova et al, 2022). The hybridization concept confers affinities for multiple targets and is expected to rejuvenate potencies, and stabilities and to minimize the side effects of existing medications.…”

DrugGym: A testbed for the economics of autonomous drug discovery

“…We score lipophilicity using Crippen’s method [58] and solubility using a gradient boosted tree trained on solubility measurements [61]. These ADME properties are often used to demarcate molecules with the potential to be orally bioavailable [76]. They are also challenging to optimize due to their strongly negative relationship [67].…”

Solubility data and solubility parameters of barnidipine in different pure solvents

“…The classical flask-shaken technique has been used as the solid-liquid equilibrium method to evaluate the solubility of barnidipine. (3) In addition, the calculation of Hansen solubility parameters (HSP) was proposed, key to help in the design of drugs. (4)(5)(6) Hansen divided the cohesive energy density (the square root of cohesive energy density is called solubility parameter, δ) into contributions from nonpolar interactions (van der Waals dispersion forces), dipole interactions and hydrogen bonding (Equation 1).…”