Design and synthesis of 3,4-methylenedioxy-6-nitrophenoxyacetylhydrazone derivatives obtained from natural safrole: new lead-agents with analgesic and antipyretic properties.

In this work, we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and antipyretic properties of new 2-(6-nitro-benzo[1,3]dioxol-5-yloxy)-acetylhydrazone derivatives (3), designed exploring molecular hybridization and isosteric replacement approaches between nimesulide (1) and carbanalogue NAH series (2) developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (4) as starting material. The evaluation of the antinociceptive properties of this series led us to discover a new potent prototype of analgesic and antipyretic agent, that is, NAH derivative 3c, named LASSBio-891, which showed to be more potent than dipyrone used as standard.

Design, synthesis, and pharmacological evaluation of new neuroactive pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives with in vivo hypnotic and analgesic profile.

The present study describes the synthesis and pharmacological profiles of four novel pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives 2-5, which were structurally designed by using the sedative and analgesic drug zolpidem 1 as lead compound. The heterotricyclic system present in the target compounds 2-5 was constructed in good yields, exploiting a regioselective hetero Diels-Alder reaction of the key azabutadiene derivative 7 and functionalized N-phenylmaleimides 9-12. Additionally, we identified that 1-methyl-7-(4-nitrophenyl)-3-phenyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8-dione derivative (LASSBio-873, 5) presented not only the most potent ability to promote sedation, which was similar to that induced by the standard benzodiazepine drug midazolam, but also potent central antinociceptive effect.

Studies on new cyclic imides obtained from aminophenazone with analgesic properties. Potent effects of a 3,4-dichloromaleimide derivative.

This paper describes the synthesis of new cyclic imides obtained by reaction with aminophenazone (CAS 58-15-1, 4-aminoantipyrine) and different anhydrides with further cyclization with acetic acid under reflux. Their structures were confirmed by spectral data (IR and NMR) and elemental analysis. The analgesic activity of the synthesized compounds was investigated initially with the writhing test in mice and the most promising compound, a 3,4-dichloromaleimide derivative (3), was analyzed using other models of nociception. The results indicated that compound 3 exerts potent analgesic activity in mice, being more active than some reference drugs. The analgesia caused by this compound was not reversed by naloxone in the writhing test. In the hotplate test, compound 3 did not increase the latency period of pain induced by thermal stimuli, confirming that it does not interact with opioid systems.

Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters, derived from natural safrole.

Anew series of antinociceptive compounds belonging to the N-acylarylhydrazone (NAH) class were synthesized from natural safrole (7). The most analgesic derivative represented by 10f, [(4'-N,N-dimethylaminobenzylidene-3-(3', 4'-methylenedioxyphenyl)propionylhydrazine], was more potent than dipyrone and indomethacin, used as standards. The NAH compounds described herein were structurally planned by molecular hybridization and classical bioisosterism strategies on previously reported analgesic NAH in order to identify the pharmacophoric contribution of the N-acylarylhydrazone moiety and investigate the structure-activity relationship (SAR) in these series.

Synthesis and analgesic profile of novel N-containing heterocycle derivatives: arylidene 3-phenyl-1,2,4-oxadiazole-5-carbohydrazide.

This paper describes recent results of a research program aimed at the synthesis and pharmacological evaluation of new heterocyclic N-acylhydrazone (NAH) compounds, belonging to the arylidene (3-phenyl)-1,2,4-oxadiazolyl-5-carboxyhydrazide (8a-p) series. These compounds were structurally planned by applying the molecular hybridization strategy on previously described arylidene 1-phenylpyrazole-4-carbohydrazide (5) derivatives, considered as lead-compounds, which present potent analgesic properties. The analgesic profile of the title compounds 8a-p, evaluated in the model of abdominal constrictions induced by acetic acid, showed that the 4-methoxybenzylidene derivatives 8c and 8k were the most active ones, exhibiting a relative analgesic activity comparable with that of dipyrone 1 used as standard.

Synthesis and analgesic properties of new 5-thioaryl pyrazole derivatives.

A new series 5-thio aryl pyrazole derivatives were proposed aiming analgesic activity. In this work, 8 new compounds of this class were synthesized using usual synthetic methodology, having as key intermediate the 3-methyl-4-nitro-5-chloropyrazole-1-phenyl derivative and subsequent reaction with several nucleophiles sulfides. Pharmacological evaluation of this series showed analgesic activity in the some extent in especially for 5-(4-bromophenyl)-thio-3-methyl-4-nitro-1-phenylpyrazole which was the most potent in this series, presenting an analgesic action comparable to that show by dipyrone.

Synthesis and analgesic properties of new 4-arylhydrazone 1-H pyrazole [3,4-b] pyridine derivatives.

Based on the principle of bioisosterism, a successful strategy in the planning of new drugs, we describe in this work the synthesis and the analgesic activity of the new functionalized arylcarbaldehyde 4-(1-phenyl-3-methylpyrazolo[3,4-b]pyridine) hydrazone derivatives 5a-m. These derivatives (5a-m) were synthesized in ca. 45% overall yield, using 4-(1-phenyl-3-methylpyrazolo[3,4-b]pyridinyl) hydrazine 6, as key intermediate. by applying classical synthetic methods to construct the aryl-hydrazone unit at C-4 of the heterocyclic system. Compound 6 was prepared from the corresponding 4-chloro-(N-phenyl-3-methylpyrazolo[3,4-b]pyridine) derivative 7 in very high yield. The antinociceptive activity of these new compounds 5a was evaluated by a test of abdominal contortions induced by 0.6% acetic acid solution i.p. in albino mice. The compounds 5f, 5g, 5j and 5k were strongly active showing a good analgesic profile.