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Published04 Mar Abstract The present work deals with the synthesis and evaluation of biological activities of 4-aminoantipyrine derivatives derived from a three-component Betti reaction.
The synthesis was initiated by the condensation of aromatic aldehyde, 4-aminoantipyrine, and 8-hydroxyquinoline in presence of fluorite as catalyst in a simple one-step protocol. The structures of synthesized derivatives were established on the basis of spectroscopic and elemental analysis. All derivatives 4 a—h were screened in vivo and in vitro for anti-inflammatory and anthelmintic activity against a reference drug, Diclofenac and Albendazole, respectively.
The screening results show that compounds 4c, 4d, 4f, and 4h were found to possess potential anti-inflammatory activity while compounds 4a, 4b, 4e, and 4g are potent anthelmintic agents when compared with reference drugs, respectively.
Introduction Multicomponent reactions MCRs have appeared as an imperative means for the construction of diverse and complex organic molecules [ 1 ].
They have intrinsic advantages over two component reactions in several aspects including the simplicity of a one-pot procedures and possible structural variation. The synthetic competence comes from several tandem bond formation reactions in MCRs, which save time, energy, and raw material.
Betti reaction is a modified type of Mannich reaction [ 2 ] which has subsequently become vital in synthetic chemistry because of C—C bond formation under mild experimental conditions.
Interest in the chemistry of Betti reaction derivatives was also strengthened as it was found to possess various catalytic and biological applications [ 3 — 5 ]. Nonsteroidal anti-inflammatory drugs NSAIDs are the most clinically important medicine used for the treatment of inflammation-related diseases like arthritis, asthma, and cardiovascular diseases [ 6 ].
However, the long-term administration of NSAID may induce gastrointestinal ulcers, bleeding, and renal disorders due to their nonselective inhibition of both constitutive COX-1 and inducible COX-2 isoforms of the cyclooxygenase enzymes [ 7 — 9 ]. Therefore, new anti-inflammatory drugs lacking those effects are being searched all over the world as alternatives to NSAIDs [ 10 ]. Due to the emerging need of improved and highly selective inhibitors of COX-2, various heterocyclic compounds are synthesized amongst pyrazole compounds and their derivatives are some of them.
It is evident from the reported literatures that compounds possessing pyrazole nuclei showed significant anthelmintic as well as antimicrobial activities [ 14 — 16 ]. Structural variations produce new physical and biological properties.
The molecular manipulation of a promising lead compound is still a major line of approach for the discovery of new drugs. Molecular rearrangement involves the efforts to combine separate groups having similar activity in one compound by eliminating or substituting new moiety to a parent lead compound. Hence, an attempt has been made in this study to condense 4-aminoantipyrine in a Betti reaction to formulate novel biologically potent moieties using fluorite [ 17 — 19 ] as an excellent catalyst.
Fluorite also called fluorspar is a natural occurring mineral composed of calcium fluoride CaF2. It may occur as transparent or translucent isometric cubic and octahedral crystals. Fluorite acts as a mild acid in the dehydration reaction and increases the reaction rate without affecting the yield of desired products. The paper deals with the synthesis of 4-aminoantipyrine derivatives via three-component Betti reaction and its assessment for biological applications, namely, anti-inflammatory and anthelmintic.
We have also investigated the biological applications of these derivatives using online cheminformatics molinspiration software. A comparison between experimental and theoretical predictions of the biological activity has enabled us to identify alternative combined pharmacophore sites structures. The main interesting task of this work is to develop robust prediction models for inhibitory properties solubility, bioavailability, etc. Materials and Methods 2.
General All the reagents and solvents are of analytical grade purchased from a commercial source and used directly. Fluorite was purchased in the form of crystalline block from an Indian supplier and hammered into pieces of 1—3 mm in size before use. All melting points were determined by open tube capillaries method and are uncorrected.
The purity of compounds was checked routinely by TLC 0. Mass spectra were recorded on a Micromass Q-T of high resolution mass spectrometer. Protocol for In Vivo Anti-Inflammatory Assessment Wistar albino rats [ 20 ] were divided into ten groups of six animals each. After one hour of the oral administration of synthesized drugs and standard drug, freshly prepared 0. Measurement of paw volume was done by means of volume displacement technique using Plethysmometer [ 21 ].
Paw volume was recorded at the interval of 0, 1, 2, 3, and 4 h after carrageenin injection. Results were expressed as an increase in paw volume in comparison with the control group. Control group was administered with normal saline water. M and data were statistically analyzed by one-way analysis of variance ANOVA and was considered as significant. Protocol for In Vitro Anthelmintic Investigation Indian earthworms of the genus and species Pheretima posthuma [ 22 ] family: Megascolecidae were used for this study.
The earthworms that are 3—5 cm in length and 0. The worms were divided into the ten groups containing six earthworms in each group. Albendazole solution was used as a standard drug and saline water as control. The anthelmintic activity was determined in six observations. The earthworms were observed for their spontaneous motility an evoked responses.
Observations were made for time taken to paralysis and death of individual worms. Paralysis was said to occur when the worms do not revive even in saline water. Death was concluded when the worms lost their motility followed by fading away of their body color. Protocol for the Synthesis of 4-Aminoantipyrine Derivatives 4 a—h A mixture of 4-aminoantipyrine 0. The reaction mixture was stirred for 10—15 min. The completion of the reaction was monitored by TLC by using mixture of ethyl acetate and hexane as mobile phase.
After completion, the reaction mixture was poured into crushed ice. The crude product and catalyst were collected on a Buchner funnel by filtration.
The crude product was purified by recrystallization from hot ethanol to get the pure product. The following are the spectral data of the synthesized compounds. Scheme 1 Synthesis of 4-aminoantipyrine derivatives via Betti reaction. Elemental analysis: calcd. Results and Discussion 3. Chemistry In order to carry out the synthesis in a more efficient way that minimizes time and the amount of catalyst, a model reaction Scheme 1 was magnetically stirred at room temperature using a naturally occurring mineral, fluorite, as a catalyst.
The catalyst was reused in at least eight reactions with no reduction in its efficiency. The structures of compounds 4 a—h were deduced from their spectral data. All other peaks in the spectra are in well agreement with the contents of functionalities in the synthesized molecules. The 1H NMR data of all compounds for the presence of aromatic protons reveal multiplets peak between 6.
The spectra showed singlet around 5. The spectral data showed a characteristic singlet around 2. Presence of singlet around A singlet for three protons around 3. All the compounds have given the satisfactory elemental analysis. Oedema formation due to carrageenin in the rat paw is biphasic event.
The initial phase is attributed to the release of histamine and serotonin. The second phase of oedema is due to the release of prostaglandins, protease, and lysosome. Subcutaneous injection of carrageenin into the rat paw produces inflammation resulting from plasma extravasations, increased tissue water, and plasma protein exudation along with neutrophil extravasations, all due to the metabolism of arachidonic acid.
The first phase begins immediately after injection of carrageenin and diminishes in two hours. The second phase begins at the end of first phase and remains through third hour up to five hours.