Comparison of Conventional and Microwave Synthesis of Phenyl-1H-pyrazoles and Phenyl-1H-pyrazoles-4-carboxylic Acid Derivatives.

BACKGROUND: Privileged scaffolds are of high importance for molecules containing the pyrazole subunit due to their broad spectrum of pharmacological activities. For this reason, a method that is more efficient needs to be developed for the preparation of pyrazole derivatives. OBJECTIVE: The purpose of this study was the optimisation of the conventional synthesis of the pyrazole ring and the oxidation of phenyl-1H-pyrazole-4-carbaldehyde to phenyl-1H-pyrazole-4-carboxylic acid through Microwave- Assisted Organic Synthesis (MAOS). METHODS: We performed a comparison between conventional synthesis and conventional synthesis with microwave heating using the synthesis method of pyrazole ring described by Finar and Godfrey and for the oxidation of phenyl-1H-pyrazole-4-carbaldehyde, the method described by Shriner and Kleiderer was used. RESULTS: MAOS reduces the reaction time to obtain all compounds compared to conventional heating. At a temperature of 60°C, 5 minutes of reaction time, and power of 50 W, the yield of phenyl-1H-pyrazoles (3a-m) compounds was in the range of 91 - 98% using MAOS, which is better than conventional heating (72 - 90%, 75ºC, 2 hours). An improvement in the yield for the oxidation reaction was also achieved with MAOS. The compounds (5a-m) were obtained with yields ranging from 62 - 92% (80ºC, 2 minutes, 150 W), while the yields with conventional heating were in the range of 48 - 85% (80ºC, 1 hour). The 26 compounds were achieved through an easy work-up procedure with no chromatographic separation. The pure products were characterised by the spectral data obtained from IR, MS, 1H and 13C NMR or HSQC/HMBC techniques. CONCLUSION: The advantages of MAOS include short reaction time and increased yield, due to which it is an attractive option for pyrazole compounds synthesis.

Dealing with frequent hitters in drug discovery: a multidisciplinary view on the issue of filtering compounds on biological screenings.

Introduction: The timely identification biologically active chemicals, in disease relevant screening assays, is a major endeavor in drug discovery. The existence of frequent hitters (FHs) in non-related assays poses a formidable challenge in terms of whether to consider these molecules as chemical gold or promiscuous non-selective reactive trash (also known as PAINS - pan assay interference compounds).Areas covered: In this review, the authors bring together expertize in synthetic chemistry, cheminformatics and biochemistry, three key areas for dealing with FHs. They discuss synthetic methods facilitating preparation of chemically diverse molecular libraries, while favoring activity in the biological space. They also survey and discuss recent computational advances in the prediction of PAINS from chemical structures. Finally, they review experimental approaches for the validation of the biological activity of screening hits and discuss alternatives for exploiting promiscuity and chemical reactivity.Expert opinion: It's essential to develop more efficient computational methods to reliably recognize PAINS in distinct molecular environments. Accordingly, advances in synthetic chemistry hold the promise to provide a better quality of chemical matter for drug discovery. Medicinal chemists should be more open to screening for hits showing biologically complex mechanisms of action rather than discarding molecules that may prove valuable as innovative disease treatments.

Development of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infections

Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phenothiazine (7) and 10-(3-(1-(3-([1,1-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-phenothiazine (12) showed respective IC50 values of 1.8 and 1.9gmL(-1) against T.cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.