The development of anticancer compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs) is a promising research area for pharmaceutical companies and research institutes. A series of 3,5-disubstituted 1,2,4-oxadiazoles, sharing common structural features with colchicine and combretastatins, was designed and synthesized for screening as antiproliferative CBSIs. All targets were submitted to National Cancer Institute (NCI), USA for screening at 10 mM in full NCI 60 cell panel. In addition, molecular docking studies were performed for the newly synthesized oxadiazole derivatives as CBSIs in β-tubulin against the β-tubulin pocket of colchicine. Also, 5a – as the most active member – was evaluated for its ability to inhibit β-tubulin polymerization against colchicine 6 as a reference standard. The targets showed significant antiproliferative activities. Amongst the series, target 5a demonstrated the broadest and most potent antiproliferative activity (positive cytotoxic effect (PCE) = 33/60 and the mean growth inhibition (MGI) for the most sensitive cell lines (33) is 24.9%. In addition, targets (5a–k) showed selective potency towards renal cancer in particular the A498 cell line. The order of potency of the three most potent targets and the standard colchicine (retrieved from NCI database) against A498 is: colchicine (GI = 84.5%) > 5a (GI = 78%) > 5d (GI = 51%) > 5f (32%). Compound 5a achieved superior binding affinity (−8.06 kcal mol⁻¹) compared with that of colchicine 6 itself, which achieved (−7.40 kcal mol⁻¹). Also, 5a showed a two-fold potent inhibitory activity of tubulin polymerization (IC₅₀: 1.18 μM) compared with that of colchicine (IC₅₀: 2.37 μM). Thus, target 5a represents a promising selective anticancer CBSI.

Background/Objectives: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. Methods: The newly synthesized compounds were analyzed with IR, ¹³C NMR, ¹H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9 and 10 were the most active, achieving IC₅₀ = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC₅₀ values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC₅₀ = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound 9 were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have apoptotic antiproliferative action as Hsp90 inhibitors.

The past decade has seen most antimalarial drugs lose their clinical potency stemming from parasite resistance. Despite immense efforts by researchers to mitigate this global scourge, a breakthrough is yet to be achieved, as most current malaria chemotherapies suffer the same fate. Though the etiology of parasite resistance is not well understood, the parasite’s complex life has been implicated. A drug-combination therapy with artemisinin as the central drug, artemisinin-based combination therapy (ACT), is currently the preferred malaria chemotherapy in most endemic zones. The emerging concern of parasite resistance to artemisinin, however, has compromised this treatment paradigm. Membrane-bound Ca²⁺-transporting ATPase and endocytosis pathway protein, Kelch13, among others, are identified as drivers in plasmodium parasite resistance to artemisinin. To mitigate parasite resistance to current chemotherapy, computer-aided drug design (CADD) techniques have been employed in the discovery of novel drug targets and the development of small molecule inhibitors to provide an intriguing alternative for malaria treatment. The evolution of plasmepsins, a class of aspartyl acid proteases, has gained tremendous attention in drug discovery, especially the non-food vacuole. They are expressed at multi-stage of the parasite’s life cycle and involve in hepatocytes’ egress, invasion, and dissemination of the parasite within the human host, further highlighting their essentiality. In silico exploration of non-food vacuole plasmepsin, PMIX and PMX unearthed the dual enzymatic inhibitory mechanism of the WM382 and 49c, novel plasmepsin inhibitors presently spearheading the search for potent antimalarial. These inhibitors impose structural compactness on the protease, distorting the characteristic twist motion. Pharmacophore modeling and structure activity of these compounds led to the generation of hits with better affinity and inhibitory prowess towards PMIX and PMX. Despite these headways, the major obstacle in targeting PM is the structural homogeneity among its members and to human Cathepsin D. The incorporation of CADD techniques described in the study at early stages of drug discovery could help in selective inhibition to augment malaria chemotherapy.

Biofilms facilitate the pathogenesis of life-threatening Pseudomonas aeruginosa infections by coating mucosal surfaces or invasive devices and offer protection from antimicrobial therapy and the host immune response, thus increasing mortality rates and financial burden. Herein, new hybrid N-acylcysteines (NAC) incorporating selected acyl groups from organic acids and their derivatives, which are capable of quenching pathogen quorum sensing (QS) systems, were designed and their antibiofilm activity and anti-QS were evaluated. N-acylcysteines (4a-h) were synthesized and characterized by ¹H NMR and ¹³C NMR, and their purity was confirmed by elemental analyses. N-(4-Hydroxy-3,5-dimethoxybenzoyl)-l-cysteine (4d) and N-(4-methoxybenzoyl)-l-cysteine (4h) showed a higher antibiofilm activity against PAO1 biofilms than the rest of the targets and the standard NAC. They showed 83 and 82% inhibition of biofilms at 5 mM and eradicated mature biofilms at 20 mM concentrations (NAC biofilm inhibition = 66% at 10 mM and minimum biofilm eradication concentration = 40 mM). This was confirmed via visualizing adherent biofilm cells on catheter pieces using scanning electron microscopy. In the same vein, both 4d and 4h showed the highest docking score with the QS signal receptor protein LasR (-7.8), which was much higher than that of NAC (-5) but less than the score of the natural agonist N-(3-oxododecanoyl)-l-homoserine (OdDHL) (-8.5). Target 4h (5 mM) decreased the expression of quorum sensing encoding genes in P. aeruginosa PAO1 strain by 53% for pslA, 47% for lasI and lasR, and 29% for filC, lowered PAO1 pyocyanin production by 76.43%, completely blocked the proteolytic activity of PAO1, and did not affect PAO1 cell viability. Targets 4d and 4h may find applications for the prevention and treatment of biofilm-mediated P. aeruginosa local infections of the skin, eye, and wounds. N-(4-Methoxybenzoyl)-l-cysteine 4h is a promising dual-acting matrix disruptive and anti-QS antibiofilm agent for further investigation and optimization.