Synthesis, characterisation and biological activity of selected pyrazoles and naphthyrides
Authors:   , Makhanya Talent Raymond 
Published: June 2021

The world continue to be threaten by various diseases from viruses, fungi and bacteria that cannot be cured. This arises due to the emergency of multidrug resistance in microorganisms hence current available drugs are becoming less potent. The solution to overcome this predicament is to further synthesize novel heterocyclic compounds which can display good therapeutic properties. Hence, this study focuses on the synthesis, characterization and biological evaluation of selected novel naphthyridinones, naphthyridines and pyrazoles. A total of 53 novel compounds were prepared by using multi-component reactions (MCRs), Povarov’s [4+2] and Povarov’s [3+2] reactions. The MCR was used for a solvent free synthesis of eight novel [1, 8] naphthyridinones from a mixture of 2-aminopicoline, various benzaldehyde derivatives and dimedone. A conventional heating protocol was used whilst the reaction was catalysed by phosphotungstic acid. The compounds were identified as 4, 8, 8-trimethyl-5- phenyl-5, 5a, 8, 9-tetrahydrobenzo[b] [1, 8] naphthyridin-6(7H)-ones with the aid of spectroscopic techniques, viz., FT-IR, NMR, EI- MS and elemental analysis. These eight compounds were screened for their anticancer activity against A549 lung cancer cells. Cell viability assays showed these compounds have a biological effect at various concentrations. Two compounds showed that good potential as an anti-proliferative agent and exhibited a dose- dependent decline in cell viability which was seen. The Povarov’s [4+2] cycloaddition reaction was used to synthesize nine novel fused indolo [1, 8] naphthyridines. Indole was used as the dienophile whilst N-aryl aldimines were selected as the diene which were produced by reacting 2-amino-4-picoline and benzaldehyde. The reaction was catalysed by indium chloride to produce 1-methyl-6-phenyl-6,6a,7,11b-tetrahydro-5H-indolo[3,2-c][1,8]naphthyridine which was characterized by FT-IR, NMR, TOF-MS and elemental analysis. Furthermore, all synthesized compounds were screened for their antimicrobial activity. The results of the bioassay demonstrated that some fused indolo [1, 8] naphthyridines exhibited good inhibitory effect with an MIC value ranging from 0.04687 to 0.09375 µM against Bacillus cereus and Staphylococcus aureus. The toxicity of the synthesized compounds were evaluated through mutagenicity test against Salmonella typhimurium TA 98 and TA100 strains. All compounds showed no mutagenic effects against Salmonella tyhphimurium TA 98 and TA 100 strains. The Povarov’s [3+2] cycloaddition was used to synthesize twenty six novel fused indolo pyrazole in the presence of a catalytic amount of indium chloride. The compounds were identified as 3- phenyl-2, 3-dihydropyrazolo [3, 4-b] indole-1(4H)-carbothioamides with the aid of spectroscopic techniques such as FT-IR, NMR and TOF-MS. All compounds were screened for their antimicrobial activity against various strains of pathogenic bacteria and fungi. These compounds showed good activity against Candida albicans, Candida utilis, and Saccharomyces cerevisiae with MIC of 1.5; 1.1 and 0.375 µM respectively. In addition, all the compounds showed no mutagenic activity against Salmonella tyhphimurium TA 98 and TA100 strains. The scope of the Povarov’s [3+2] reaction was further investigated using isoniazid to synthesise ten novel nicotinyl fused indolo pyrazoles in the presence of a catalytic amount of indium chloride. These compounds were identified as (3-phenyl-2,3- dihydropyrazolo[3,4-b]indol-1(4H)-yl)(pyridin-4-yl)methanone with the aid of spectroscopic techniques such as FT-IR, NMR and TOF-MS. All compounds were screened for their antimicrobial activity against various strains of pathogenic bacteria and fungi. The synthesized compounds showed weak activity against Streptococcus faecalis, Micrococcus luteus and Bacillus coagullans with a zone inhibition diameter of 9 mm and MIC of 0.75 µM. Furthermore, all synthesized compounds were tested for their toxicity against Salmonella tyhphimurium TA 98 and TA100 strains: none showed mutagenic activity.