Pyrazole

Pyrazole are potent medicinal scaffolds and exhibit a full spectrum of biological activities. This review throws light on the detailed synthetic approaches which have been applied for the synthesis of pyrazole. This has been followed by an in depth analysis of the pyrazole with respect to their medical significance. This follow-up may help the medicinal chemists to generate new leads possessing pyrazole nucleus with high efficacy.

Pyrazole is a five-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions as represented by the molecular formula C3H4N2. It is a weak base, with pKb 11.5 (pKa of the conjugated acid 2.49 at 25°C). Due to its composition and unique pharmacological effects on human beings, they are classified as alkaloids. 1-pyrazolyl-alanine was the first natural pyrazole isolated from watermelon seeds in the year 1959.

It reported to possess a wide range of biological activities in literature such as anti-microbial, anti-fungal, anti-tubercular, anti-inflammatory, anti-convulsant, anticancer, anti-viral, angiotensin converting enzyme (ACE) inhibitory, neuroprotective, cholecystokinin-1 receptor antagonist, and estrogen receptor (ER) ligand activity, etc. Many pyrazole derivatives has already found their application as nonsteroidal anti-inflammatory drugs clinically, such as anti-pyrine or phenazone (analgesic and antipyretic), metamizole or dipyrone (analgesic and antipyretic), aminopyrine or aminophenazone (anti-inflammatory, antipyretic, and analgesic), phenylbutazone (anti-inflammatory, antipyretic mainly used in osteoarthritis, rheumatoid arthritis, spondylitis, Reiter's disease), sulfinpyrazone (chronic gout), and oxyphenbutazone (antipyretic, analgesic, anti-inflammatory, mild uricosuric). In this review, our main intention is to emphasize on the different biological activities exhibited by pyrazole moiety.

For a very long time, the usefulness and great therapeutic value of pyrazole nucleus have been recognized and widest range of activities of this nucleus evaluated. However, as the first synthetic organic compound having pyrazoline-5-one nucleus, to find use as an important drug. Phenylbutazone as a prototype of pyrazolidinedione is a very potent anti-inflammatory agent, but its use is now banned in some countries. Later on, many modifications of pyrazole nucleus were attempted and several compounds have been synthesized which serves as the basis for the treatment of different diseases like-inflammation, pain, cancer, tuberculosis, and diseases caused by bacteria.

Synthesized a new series of pyrazole, isoxazole, benzoxazepine, benzothiazepine, and benzodiazepine derivatives by the multi-component cyclo-condensation reaction of 1-phenyl-3-(2-(tosyloxy)phenyl)propane-1,3-dione, DMF dimethyl acetal, and hydrazine or hydroxylamine hydrochloride or 2-aminothiophenol or 2-aminophenol or benzene-1,2-diamine by MW technique in aqueous media. Compound 3a screened for their anti-inflammatory activity using indomethacin as the standard drug was found to be potent.

Low quality of life and life-threatening conditions often demand pharmacological screening of lead compounds. A spectrum of pharmacological activities has been attributed to pyrazole analogs. The substitution, replacement, or removal of functional groups on a pyrazole ring appears consistent with diverse molecular interactions, efficacy, and potency of these analogs. This mini-review explores cytotoxic, cytoprotective, antinociceptive, anti-inflammatory, and antidepressant activities of some pyrazole analogs to advance structure-related pharmacological profiles and rational design of new analogs. Numerous interactions of these derivatives at their targets could impact future research considerations and prospects while offering opportunities for optimizing therapeutic activity with fewer adverse effects.

This mini-review explores selected activities and structural modifications of some pyrazole analogs. The available data on the concentration of analogs required for 50% inhibition (IC50), equilibrium dissociation constant for the inhibitor (Ki), the dose that elicited 50% of the maximum possible effect (ED50), ulcerogenic index (UI), or selectivity index (SI) are provided to further comparative discussions on their affinity, efficacy, and potency. As the present review is limited to selected biological activities, the author’s considerations, and future perspectives on some representative analogs, additional references are listed for the aspects that are out of the present scope.

The cytotoxic effects of some pyrazole analogs against specific cell lines including human breast cancer cells (MDA-MB-231 and MCF-7) appear promising to the development of anticancer drugs (Kamel, 2015). Compound 1 containing a distal pyrazole ring and sulphonyl moiety decreased the viability of MCF7 (IC50 = 39.70 µM). Since caspases play different roles in cellular survival, differentiation, and proliferation process, specific caspase inhibition by compounds 1–3 suggests a safety profile. Potent antiproliferative activity (IC50 = 0.26 μM) and mitogen-activated protein kinase inhibition (MEK, IC50 = 91 nM) have been attributed to methyl and ortho-fluorine groups on pyrazole carboxamide of compound 5. This result suggests suppression of abnormal signaling of the MEK-dependent pathways. In the docking assay, the contribution of the 1,3-diphenyl-1H-pyrazole to hydrophobic interactions (Val 82, Ala 95, Val 127, Met 143, Met 143, and Leu 197 of the ATP-binding pocket) and MEK inhibition was considered significant. Recently, a thiazole moiety was attached to the pyrazole ring and assayed against different cancer cell lines. Relatively high cytotoxic efficacy of compounds 6–8 (IC50 = 14.32, 11.17, and 10.21, respectively) against MCF-7 supports the antitumor role of the thiazole moiety. However, the specificity of the cytotoxic potential and emerging resistance still need to be extensively evaluated.

As some analogs are considered potent IC50 < 100 nM; mild IC50 > 10,000 nM cytotoxic or noncytotoxic on some cell lines, and others elicit cyto- or neuroprotection. The restoration of redox homeostasis or prevention of oxidative stress, inflammation, glycation, and vascular injury is key to neuroprotection. Chemically diverse pyrazole analogs have shown promising cellular or neuronal protections. The bulky dicyclohexylamide (9), smaller dimethylamide (10), and aminophenyl (11) (pyrazole analogs with sterically hindered substituents on amide) attenuated microglia-mediated neurotoxicity (IC50 = 10–50 µM) better than compound 12 (IC50 = 100 µM) with high susceptibility to electrophilic displacement . This compound contains an allyl group on an electron-deficient amide. Suppression of toxin-induced microglia overactivation offers a therapeutic opportunity capable of halting the progression of reactive oxygen species–induced neurodegenerative disease. The electron-withdrawing substituents such as para-bromo on the aldehyde aromatic ring (13) elicited higher neuroprotective activity than the electron-donating substituent. This activity involves the inhibition of glycogen synthase kinase 3β (GSK3β; IC50 = 3.77 µM) and induction of nuclear factor (erythroid-derived 2)–like 2 (Nrf2; luciferase activity = 3–30 µM). As regulators of cellular responses, both GSK3β and Nrf2 are key neurodegenerative targets.