Rapid and Economic Access to Some NSAIDS-Based Bioactive Heterocycles

euse ofmicrowave energy for the synthesis is considered as one of the alternate strategies.e present work includes the synthesis of some newer 2,5-disubstituted-1,3,4-oxadiazole analogues using both conventional and alternate rapidmethods.e conventional method involves the synthesis of the target molecules by using cyclodehydrating agent like POCl3, while the other method consists of using some catalytic reagents like PbO2. Also, the short reaction time provided by microwave synthesis makes it ideal for the reaction. Hence, this project describes an efficient and operationally simple method for the microwave-assisted synthesis of some bioactive heterocycles based on NSAIDs.


Introduction
Synthetic methodology, as the building block of organic synthesis, continuously seeks for new reagents, better reaction conditions, and the usage of newer catalysts for more efficient and selective synthesis.e increasing environmental consciousness throughout the world has put a pressing need to develop an alternate synthetic approach for biologically and synthetically important compounds [1].e best option to accelerate these synthetic processes is the use of microwave irradiation [2].e use of Microwave-Assisted Organic Synthesis (MAOS) in synthetic chemistry reduces reaction time and increases product yield.Some of the major advances in chemistry have also been observed in the area of catalysts.Modern catalysts provide highly selective routes to synthesize chemical products [3].
Nonsteroidal anti-in�ammatory drugs (NSAIDs) are essential compounds to treat sign and symptoms of in�ammation and pain.ey exert their effect mainly through inhibition of cyclooxygenases (COXs), the key enzyme in prostaglandin (PG) biosynthesis.But the ulcerogenic potential limits their use.e ulcerogenic nature of NSAIDs is attributed to free -COOH group present therein.e literature is �ooded with different approaches used to modify free -COOH thereby modifying the activity of the parent NSAIDs [4].In the present work, as shown in the Figure 1, this free -COOH group is modi�ed by converting it into 1,3,4-oxadiazole ring which is toxophoric in nature and acts as bioisostere [5,6].
Heterocyclic compounds are proven backbone for the discovery of many bioactive compounds.Molecules containing a 1,3,4-oxadiazole scaffold have shown broad range of biological activities like antibacterial, antitubercular, antifungal, analgesic, and anti-in�ammatory properties [7,8].Consequently, the synthesis of such heterocycle has attracted considerable attention and a wide variety of methods have been used for its assembly [9].By far the most common strategy involves the dehydrative cyclization of diacylhydrazides, usually with strongly acidic reagents such as POCl 3, SO 2 Cl, P 2 O 5 , H 2 SO 4 , or PPA [10].Unfortunately, most of the procedures which have been described for this reaction entail using toxic reagents or solvents, long reaction times, and so forth.Keeping this in view, the present work aims at the synthesis of some newer 2,5-disubstituted- analogues based on NSAIDs using both conventional and rapid alternate methods.Conventional method involves synthesis of the target molecules by using cyclodehydrating agent like POCl 3 , while alternate method consists of use of some newer, selective, catalytic reagents like lead oxide.en the comparison based on the rapidness, cost-effectiveness, and ecofriendliness is done to establish the most effective method.Furthermore, the compounds were evaluated for antimicrobial and analgesic activities to check their biological potential.Mass (m/e): 320 (M + ), 244 (M-77).Mass (m/e): 467.1(M + ), 391(M-77).

Chemistry.
A novel series of NSAIDs-based 1,3,4oxadiazoles was synthesized using two methods (Method A and Method B).Method A was conventional method and Method B was based on microwave-assisted synthesis using novel catalytic reagent.e basic theme in these synthetic strategies was to synthesize NSAID-based pharmacologically important 1,3,4-oxadiazoles in economic and rapid manner.e aim was successfully achieved by developing a convenient, rapid, and cost-effective method.
e acid hydrazides (3a/3b) were prepared by esteri�cation of (1a/1b), followed by the treatment of each separately with hydrazine hydrate in absolute ethanol.Various 2-aryl substituted-1,3,4-oxadiazole derivatives (6a-6j) were further synthesized using both methods.e purity of synthesized compounds was established by TLC using appropriate solvent system.ey were characterized by IR, 1 H NMR, and mass spectroscopic techniques.e appearance of -C=O str at >1730 cm −1 in IR spectrum showed the formation of ester.e hydrazide formation was also shown by IR spectra as the -C=O str, amide was seen around 1635-1650 cm −1 .
Strong peaks in the range of 1250-1000 cm −1 attributed to oxadiazole ring.Few of these compounds were further con�rmed by their mass spectra.

Comparison between Synthesis by Conventional (Method A) and Alternate Methods (Method B).
A comparison of these two methods was carried out on the basis of fundamental principles and concepts of green chemistry.
(1) Yield and Purity.Newly synthesized oxadiazole compounds, their yields, and physical characteristics are compared in Tables 1 and 2. From these tables, it becomes apparent that yields of compounds obtained by cost-effective alternate route (Method B) were slightly higher (10-15% more) than the conventional route (Method A).However, as desired, their physical constants remain the same by both methods.
(2) Reaction Time.is approach shortened the reaction time signi�cantly.In Method A, 8-9 h were required to yield the desired product, whereas Method B required maximum 3 h to complete the same reaction.Hence, Method B can be considered as faster than the Method A with respect to time.
(3) Minimization of Energy Consumption.It is observed that Method B increases the yield and decreases the duration of the time required for the reaction.e use of microwave helped to reduce the thermal and mechanical energies.It also helped to reduce the wastage of other resources; for example, continuous 8 h water supply for the reaction was required in Method A, while Method B required only 3 h to give the same desired product/s.
Hence, reducing the unnecessary usage of important resources like water, electricity resulted in minimization of energy consumption.
(4) Environmental Quotient.Effect of chemicals on the surrounding environment is one of the important aspects of the ecofriendly and reliable chemistry.In Method A, the reagent used (POCl 3 ) is hazardous and requires precaution in handling.Also, HCl gas which evolves during the reaction is toxic to environment and to human health.Hence, the use of POCl 3 is not considered as ecofriendly.On other side, PbO 2 (Method B) increases the conversion and selectivity of the reaction.
Considering all the previous factors, it can be �rmly said that Method B is economic, safe, and rapid synthetic method to synthesize the compounds mentioned herein.

Evaluation of Antimicrobial and
Analgesic Activity for antibacterial activity of all the synthesized compounds was determined by agar plate method.e standard used for the study was Cipro�oxacin.e results for antibacterial activity are reported in Table 3. ese compounds showed comparable activity with that of standard.Compounds with Aceclofenac backbone (6f-6j) exhibited excellent antibacterial activity against both tested bacteria, whereas Ibuprofen derivatives (6a-6e) were found to be selective against S. aureus, a gram-positive bacteria.ese compounds were also screened in vitro for their antifungal activity against C. albicans, A. niger using agar plate technique and �uconazole as standard.e screening results for antifungal activity are given in Table 4, which indicates that all compounds exhibit moderate to excellent activity against C. albicans and A. niger, respectively.

Pharmacological Evaluation
(1) Acute Toxicity [19].Acute toxicity studies were conducted according to the OECD Guideline 425 using Up and Down the LD 50 value of majority of the compounds was found to be more than 500 mg/Kg, which make them safe for oral administration.One tenth dose of this value was selected as the therapeutic dose for the further evaluation of peripheral analgesic activity.
(2) Analgesic Activity [20,21].Peripheral analgesic activity of the compounds (6a-6j) was performed by using acetic acid-induced writhing test in mice.e analgesic activity was evaluated using Ibuprofen and Aceclofenac as standards.e results emphasized that all compounds possess signi�cant analgesic activity.e analgesic effect of compound 6e was found to be even better than Ibuprofen, while compounds 6h and 6j showed comparable activity with standard Aceclofenac.Data analyzed by one-way ANOVA followed by Dunnett's Multiple-Comparison Test (  6), * * *   0.05 signi�cant from control, is given in Table 6.

Conclusion
Ideally chemical reactions should proceed with quantitative yield, low costs, and generating no waste.e use of techniques like microwave irradiation and proper catalytic reagents will impact greatly on the �eld of medicinal chemistry.Implementation of this in the pharmaceutical and medicinal chemistry sector will lead to inexpensive drugs and sustainable development of both human and surrounding.is will ultimately result in improved quality of life for the bene�t of human welfare.is study opens up a new area of cost-effective synthesis of biologically active 2,5-disubstituted-1,3,4-Oxadiazole compounds.e further investigation in terms of largescale synthesis and industrial utility of this method could be evaluated.
). Mol.Formula: C 24 H 19 Cl 2 N 3 O 3 ; Mol.Wt.: 468.33; mp ( ∘ C): 80-83; IR (KBr, cm −1 ): was then cooled to room temperature.Lead oxide (1.0 g) was added into it under stirring.e temperature was raised to 100 ∘ C and stirred at the same temperature for 120 min at 560 watt.It was then hot �ltered to remove the �bO 2 and allowed to attain the room temperature and then poured onto ice-cold water.e solid, thus separated was �ltered, dried, and puri�ed by column chromatography (Silica gel, Ethyl acetate/Hexane 1 : 3) to afford the compounds.
procedure.Swiss albino mice (female) weighing between 20 and 30 g were given orally a particular dose say 175 mg/kg and observed for a period of 48 hrs for any mortality.e subsequent doses were then increased or decreased by a progression factor depending on its lethality.From