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Synthesis, Characterization of Microwave assisted Novel functionalized Pyrimido pyrimidine– tethered to benzothiazole Derivative and their Pharmacological Screening

Priti V. Patel, Sarika P. Patel^*and Keyur Bhatt

Department of Chemistry, Ganpat University, Kherva, Mehsana, Gujarat, India.

Corresponding Author: Email: spp04@ganpatuniversity.ac.in

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ABSTRACT:

There is a constant need to synthesise new and desired compounds. The current study focusses on the two-step, microwave-assisted three-component synthesis of new lead compounds, specifically 5-phenyl-3,5-dihydro-4H-benzothiazolo[3,2-a] pyrimido[4,5-d] pyrimidinone. Target molecules were verified using a variety of spectral techniques for analysis, such as Mass, IR, ¹H and ¹³C NMR spectrometry. The synthetic derivatives' antimicrobial abilities were measured. The Broth Dilutionmethod was utilised to measure their minimum inhibitory concentration activity against both Gram-negative as well as Gram-positive bacteria and fungi. There are several advantages to this protocol. outstanding yields, a quick reaction,simple workup, and no need for column chromatography. Both traditional methods and microwave-assisted irradiation were used to establish the mentioned reactions.

KEYWORDS:

Amino benzothiazole; Benzothiazolo-pyridopyrimidine; Biological exertion; Fused Pyrimido-benzothiazole; Microwave-assisted technique

Introduction

Heterocyclic compounds are the cyclic compounds which contain one or more different elements (such as nitrogen, oxygen, sulphur, phosphorus, silicon and selenium) other than carbon in their ring structure. Heterocyclic elements have an important role in our everyday existence. Heterocycles include the vast majority of biologically active agrochemicals and pharmaceuticals.In nature, they are widely dispersed. Heterocyclic ring systems are found in a wide range of substances, including alkaloids, antibiotics, vitamins, essential amino acids, haemoglobin, hormones, chlorophyll, and many synthetic medications and dyes.Because of their unique chemical reactivity and ability to act as easy convenient structures for adding physiologically active substituents, heterocyclic compounds are highly suitable for use as pharmaceuticals.Because of their many pharmacophoric qualities, including antimicrobial, antifungal, anti-malarial, anti-inflammatory, antiviral, and anticancer effects, among many others, heterocyclic compounds with nitrogen and sulphur atoms are crucial in the field of pharmaceutical chemistry. The advent of combinatorial or “library” techniques transformed the process of developing new leads for drug design and structure function relationship studies. “The developer of green chemistry covers the need for innovations in chemical manufacturing to advance a sustainable future”.¹According to the literature, a lot of researchers have recently employed the MCR strategy to synthesise various benzothiazole[3,2-a] pyrimidines. In light of these attributes, the design and synthesis of novel hybrid molecules incorporating both pyrimido[4,5-d]pyrimidine and benzothiazole cores offer a promising strategy for the development of potent therapeutic agents. The fusion of these two pharmacophores is expected to result in synergistic effects, potentially leading to enhanced efficacy and target specificity. This study focuses on the synthesis and characterization of a novel functionalized pyrimido[4,5-d]pyrimidine tethered to a benzothiazole derivative, aiming to explore its structural features and evaluate its potential for further biological investigations. There have been studies on multicomponent reactions that involve aldehydes, 2-amino-benzothiazole, and β-keto ester using several kinds of catalysts, including PdCl₂, nano-Fe₃O₄@SiO₂-TiCl₃, Fe₃O₄/cellulose/Cu (II), Fe₃O₄/nano-kaolin/Ti⁴⁺, Fe₃O₄/nano cellulose/ BF₃, FeFe₃ and AlCl₃.^2-8 thiazolo [3,2-a] pyrimidine was synthesised using a microwave method that was reported under clean conditions. The method of column chromatography was used to purify the resultant compounds, but less than 90 percent of the desired products were obtained.⁹Even so, appropriate sustainable and environmentally friendly procedures are still needed for pyrimido[4,5-d] pyrimidinone tethered benzothiazole derivatives under green conditions. This could be the cause of the lower number of side products that are frequently produced by reactions carried out using microwave irradiation at an optimal reaction temperature as opposed to reaction when heated conventionally, during which the reaction temperature is frequently suboptimal.^10-13

In pursuit of green methodologies, Inspired by the results of the previously published study.^14-15 Here, we describe the application of a microwave-assisted method to create new derivatives of several functionalised benzothiazole[3,2-a] pyrimidines through a reaction between malononitrile and 2-amino-benzothiazole with various aldehyde using ammonium acetate as an efficient catalyst in methanol solvent under microwave assisted and This paper presents a rapid and effective response of various benzothiazole[3,2-a] pyrimidines derivative with formic acid for the synthesis of 5-phenyl-3,5-dihydro-4H-benzothiazolo[3,2-a] pyrimido[4,5-d] pyrimidinone derivatives with sulphuric acid catalysed significantly improved output and a quick reaction time is presented in order to create novel structural motifs with encouraging bioactivity.

Result And Discussion

In Step 1 of our study, we screened for the presence and absence of various catalysts in the designs reaction that involved benzaldehyde(1a), malononitrile(2), and 2-aminobenzothaizole(3). Spectral analysis using ¹H NMR and ¹³C NMR validated each screening procedures. We found that 36% of the end result was within 60 minutes during the reflux temperature without the use of any catalyst, based on examining results (Entry 1 in Table 1). The above-described reaction is carried via one step.i.e. In the reaction of 1a and 2, benzylidene malononitrile was not separated. However, the addition of 3 resulted in the creation of an intermediary at room temperature that was subsequently microwave-exposed, producing product 4a. It indicated how 2-amino benzothiazole its own behaved as a catalyst in the Knoevenagel condensation of malononitrile and benzaldehyde. Therefore, we experimented with various catalysts to boost the yield, and the outcomes are shown in Table 1 and observed that a 53% yield was generated when Et₃N was used for a catalyst output at 10 and 20 mol% (Entry 2 and 3 in Table 1). improving the catalyst’s amount had no impact on the output of 4a. After that, using various salts of ammonium as a catalyst (they are listed entry 4-8 in Table 1), we were able to produce 59% yield of ammonium acetate in 30 minutes at irradiated microwave. The use of ammonium acetate 30 mol% generated the most effective outcomes achieved (number of 11 in Table 1), yielding an amazing 89% of the end result within only eight minuteswe looked into various solvent for the chemical process (Entries 1–7 in Table 2) and discovered overall, Ethanol was the best fluid for solvents because the end result residue split while heated and there was no need for further purifying beyond washing it with hot ethanol. While the reaction did not proceed with water (Entries 1 in Table 2), After cooling, under reaction with methanol, n-propanol, n-butanol and DCM (dichloromethane)(Entries 2,4,5 and 6 in Table 2), the end result residue became separated, with very low yields of 27%, 26% ,16%, and 53% respectively Table 2 shows the findings of our additional investigation into the range and versatility of aromatic aldehydes compounds in this multicomponent reaction. TLC showed that the reaction was finished while the solution of THF and DMSO were employed as solvents, however even after cooling, the result remained undifferentiated. This might be because, under ideal reaction conditions, such as the reaction of Compounds 1 and 2 at room temperature with ethanol as the solvent and 30 mol% catalyst were very soluble in these solvents. Compound 3 was then added, and the mixture was refluxed or microwave-irradiated during the necessary amount of time, the products were highly soluble in these solvents.

lately we have focused on synthesising specific heterocyclic compounds with expected biological activity under microwave-assisted conditions that are both environmentally friendly and time-efficient.¹⁶ The originally characterised compounds 4a–l, 5a–l were re-synthesised using microwave stimulation in order to improve reaction yields and shorten reaction times. Reaction yields were enhanced by 15–25% as opposed to the traditional approaches, and reaction durations significantly shortened, according to the findings for both MW-assisted and Conventional processes, which appear in Table 3.

Table 1: Screening of the catalyst for the model reaction^a. (step-1)

Entry	(MW irradiation) Conditions
Entry	Catalyst	Amount mol% of Catalyst	Solvent	Time (min)	Yield (%)
1	–	–	Ethanol	60	36
2	Et3N	10	Ethanol	60	53
3	Et3N	20	Ethanol	60	53
4	(NH₄)₂CO₃	20	Ethanol	30	38
5	NH₄Cl	20	Ethanol	120	no reaction
6	(NH₄)₂SO₄	20	Ethanol	120	no reaction
7	AcOH	20	Ethanol	120	no reaction
8	NH₄OAc	10	Ethanol	30	59
9	NH₄OAc	20	Ethanol	25	68
10	NH₄OAc	25	Ethanol	20	76
11	NH₄OAc	30	Ethanol	8	89
12	NH₄OAc	35	Ethanol	8	89

Table 2: Solvent screening for the model reactiona. (Step-1)

Entry	Conditions		Yield (%)
Entry	Solvent	Time(min)	Yield (%)
1	Water	35	no reaction
2	Methanol	30	27
3	Ethanol	4	89
4	n-Propanol	38	26
5	n-Butanol	35	16
6	DCM	12	53
7	Ethanol: Water (1:1)	30	68

^a Reaction conditions: Catalyst (30 mol% NH₄OAc), 1a-l (5 mmol), 2 (5 mmol), 5 mL of solvent swirled at room temperature, following the addition of 3 (5 mmol) dissolved in five millilitres of solvent and microwave-irradiated.

Table 3: Evaluation of the Efficiency of Conventional and Microwave (MW) Processes of the Production of Pyrimidine and Pyrimidine-Pyrimidine Derivatives 4a-l, 5a-l.

Compound

MW irradiation Method A

% of Yield Time (min)

Conventional Condition Method B

% of Yield Time (hour)