Nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs are traditional medicines for the treatment of inflammation, yet associated with serious side effects. Hence, the need for discovering novel compounds with valuable clinical benefits is of great importance. In this study, 18 derivatives of p-nitrophenyl hydrazones were docked against COX-2, 5-LOX, and H+/K+ ATPase, followed by predicting their drug-likeness and absorption, distribution, metabolism, and excretion (ADME) properties. From the docking analysis, 1-(4-nitrophenyl)-2-[(3,4,5-trimethoxyphenyl)methylidene]hydrazine (3), 4-hydroxy-2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]thiochroman-1,1-dioxide (6), 4-methoxy-2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]thiochroman-1,1-dioxide (8), 2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]-4-(trifluoromethyl)thiochroman-1,1-dioxide (11), 4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]benzenesulfonamide (13), 4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]-3-(trifluoromethyl)benzenesulfonamide (14), 5-methyl-6-{4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]phenyl}-2,3,4,5-tetrahydropyridazin-3-ol (16), and 5-methyl-6-{4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]phenyl}-4,5-dihydropyridazin-3(2H)-one (17) showed promise as potent multi-target inhibitors of COX-2, 5-LOX, and H+/K+ ATPase. These compounds are less COX-2 selective than the control (celecoxib). “Drug-likeness” analysis passed Lipinski's, Egan's, Veber's, Muegge's, and Ghose's rules. The compounds also passed Pfizer and GSK rules, as well as golden triangle's rule for identification of potent and metabolically stable drugs. The pharmacokinetic profiles of the compounds were excellent, safe, and compliant with their potential anti-inflammatory activity. The results of the study can be used for future optimization of those derivatives for better molecular interactions against COX-2, 5-LOX, and H+/K+ ATPase, and inflammation-effective inhibition.

We designed novel p-nitrophenyl hydrazones as multi-target inhibitors of COX-2, 5-LOX, and H+/K+ ATPase in a bid to overcome side effects associated to NSAIDs and coxibs. Specifically, compounds 1-(4-nitrophenyl)-2-[(3,4,5-trimethoxyphenyl)methylidene] hydrazine (3), 4-hydroxy-2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]thiochroman-1,1-dioxide (6), 4-methoxy-2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]thiochroman-1,1-dioxide (8), 2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]-4-(trifluoromethyl)thiochroman-1,1-dioxide (11), 4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]benzenesulfonamide (13), 4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]-3-(trifluoromethyl)benzenesulfonamide (14), 5-methyl-6-{4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]phenyl}-2,3,4,5-tetrahydropyridazin-3-ol (16), and 5-methyl-6-{4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]phenyl}-4,5-dihydropyridazin-3(2H)-one (17) indicated promise as potent multi-target inhibitors of COX-2, 5-LOX, and H+/K+ ATPase with potential anti-inflammatory activity devoid of adverse effects of NSAIDs. Interactions with important amino acids which are key for ant-inflammatory activity and proton pump inhibition were noticed. All the compounds are less COX-2 selective compared to celecoxib. These compounds in addition have shown druglike physicochemical properties, passed Lipinski’s, Egan’s, Veber’s, Muegge’s and Ghose’s rules for druglike small molecules and orally bioavailable drugs. The compounds also passed golden triangle’s rule for potent and metabolically stable drugs. Also, these compounds passed Pfizer and GSK rules. The compounds also indicated excellent pharmacokinetic profiles complementing their potential anti-inflammatory activity with apparent safety profiles.

We conducted a comparative study on the development of two synthetic methods. The solvent-free synthesis is a green chemistry method developed in a bid to ameliorate environmental adverse effects of the conventional solvent-based synthesis. The synthesis of novel dichloro and polymethoxy p-nitrophenylhydrazones through solvent free technique gave moderate to high yields which were however lower than those of the solvent-based method. The established solvent-free approach has several benefits, including universality and simplicity of the approach, catalyst-free conditions, non-use of an organic solvent, quick reaction time, fast and efficient workup, and un-solvated pure products in moderate to high yields.

We designed novel p-nitrophenyl hydrazones as multi-target inhibitors of COX-2, 5-LOX, and H+/K+ ATPase in a bid to overcome side effects associated to NSAIDs and coxibs. Specifically, compounds 3, 6, 8, 11, 13, 14, 16, and 17 indicated promise as potent multi-target inhibitors of COX-2, 5-LOX, and H+/K+ ATPase with potential anti-inflammatory activity devoid of adverse effects of NSAIDs. Interactions with important amino acid which are key for ant-inflammatory activity and proton pump inhibition were noticed. All the compounds are less COX-2 selective compared to celecoxib. These compounds in addition have shown druglike physicochemical properties, passed Lipinski’s, Egan’s, Veber’s, Muegge’s and Ghose’s rules for druglike small molecules and orally bioavailable drugs. The compounds also passed golden triangle’s rule for potent and metabolically stable drugs. Also, these compounds passed Pfizer and GSK rules. The compounds also indicated excellent pharmacokinetic profiles complementing their potential anti-inflammatory activity with apparent safety profiles.

Malaria remains a febrile infection of public health concern in many countries especially tropical countries in Africa, and certain countries in Southern and North America such as Brazil, Costa Rica, Mexico, Dominican Republic, Colombia, and Ecuador. Hence this has made research into this area paramount. Acetophenones are active fragments in many compounds with promising antimalarial activity, such as chalcones. In this study, 3,5-diprenyl acetophenone (I) and 5-diprenyl (II) acetophenone were synthesized using an aromatic substitution reaction and tested for in-vivo antimalarial activity. The in-vivo antimalarial potential of the synthesized compounds was carried out using a curative model with plasmodium berghei infected mice. At all the three doses tested; 25 mgkg-1, 50 mgkg-1 and 100 mgkg-1 3,5-diprenyl acetophenone (I) showed promising activity with percentage inhibition of 68.03%, 65.16% and 69.75% respectively demonstrating dose-dependent activity. However, 5-prenyl acetophenone (II) only displayed significant activity (72.12% inhibition) at a dose of 100 mgkg-1. The two compounds passed Lipinski’s rule of five and thus drug-like candidates.