Letters in Organic Chemistry - Volume 18, Issue 9, 2021

Synthesis of heterocyclic compounds containing quinoline scaffold gained significant attention of organic chemists due to their importance as a therapeutic agent in the pharmaceutical industry. Quinoline molecules exhibit extensive biological activities, a few of which are antiviral, anti-inflammatory antibacterial, antifungal, antiproliferative, anthelmintic and anticonvulsant. A variety of synthetic routes has been developed for construction compounds bearing the quinoline nucleus due to its broad spectrum of pharmacological activities. This review describes recent development in transition metal mediated synthetic protocols of these important heterocycles by the formation of quinoline rings or by substitution of quinoline rings, including both modified conventional name reactions and novel routes with highly functionalized quinoline products.

Ischemia reperfusion injury is responsible for impaired graft functioning in organ transplants, cerebral dysfunction, ischemic heart diseases, systemic inflammatory response syndrome, gastrointestinal dysfunction, and multiple organ dysfunction syndromes. Intracellular pH is critical for cell survival in ischemia reperfusion injury. Sodium hydrogen exchanger I and carbonic anhydrase II are critical in the regulation of intracellular pH. Inhibition of sodium hydrogen exchanger I and carbonic anhydrase II during reperfusion is found to ameliorate ischemia reperfusion injury separately. An attempt is made to synthesize dual inhibitors of sodium hydrogen exchanger and carbonic anhydrase to have better potential drug molecule in ischemia reperfusion injury treatment. The hydroxybenzotriazole is considered as a central pharmacophore for this dual activity and 12 derivatives are synthesized. All derivatives are tested for sodium hydrogen exchanger I and carbonic anhydrase II inhibitory activity. The tosylate derivative (12) is found to be the most potent derivative with IC50 158.7± 8.4 μM for carbonic anhydrase II and 31.07 ± 1.06 μM for sodium hydrogen exchanger I. Although the potency is less than standard drugs but this is the first report of dual inhibitor of carbonic anhydrase II and sodium hydrogen exchanger.

5-(7-Methyl-2-propyl-1H-benzo[d]imidazol-5-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols (6a-i) have been synthesized from key intermediate 7-methyl-2-propyl-1H-benzo[d]imidazole-5- carbohydrazide(3). The hydrazide was treated with different aryl isothiocyanates to give corresponding thiosemicarbazone derivatives, which underwent cyclization in 4N sodium hydroxide to afford the corresponding title compound. All the compounds were evaluated for their in vitro antioxidant and in vivo anti-inflammatory activity. From the results, compounds 6b and 6e showed potential antioxidant and anti-inflammatory activity. The biological data was further supported by molecular docking studies, which revealed the binding pattern and the affinity of the molecules in the active site of COX-2.

A one-pot three component synthesis of a series of new gramine derivatives was designed and achieved via reactions of indole or N-methylindole with aromatic aldehyde and heteroaryl amines at 80-110 °C for 10-24 hours in an oven under solvent- and catalyst-free conditions providing an efficient, convenient and green method for the syntheses of a series of indol-3-yl- and N-methylindol-3-yl-1-aminopyrimidin-2-ones/thiones. So, fourteen novel gramine derivatives were conveniently synthesized and characterized by elemental analyses, FT IR, ¹H and ¹³C NMR spectroscopic measurements.

Cancer is one of the leading causes of death. The aim of the present study was to synthesize and investigate the anticancer and antioxidant activities of some 3,5-bis(substituted benzylidene)- 1-ethylpiperidin-4-one analogues (4a-g). The 3,5-bis(substituted benzylidene)-1-ethylpiperidin-4-one analogues (4a-g) were prepared from the precursor, piperidin-4-one hydrochloride (1). The initial step involved the synthesis of intermediates, 3,5-bis(substituted benzylidene)piperidin-4-one analogues (3a-g) followed by their ethylation with C2H5I in acetone and K2CO3 to obtain the title compounds (4a-g). The Fourier transform infrared (FTIR), nuclear magnetic resonance (¹H & ¹³C NMR), mass spectrometry and microanalysis were used to characterize the title compounds (4a-g). All the compounds were further evaluated for their anticancer activity by SRB assay and NCI US protocol, while the antioxidant activity was evaluated by DPPH free radical assay. All the title compounds (4a-g) were subjected to molecular docking studies against EGRF tyrosine kinase, a potential target for anticancer agents, to study the possible mode of interaction of our compounds with the molecular target. The compound 4g showed significant anticancer activity with GI50 of 28.2 μM against MCF-7 (Breast cancer cell line). The antioxidant activity of compound 4g (IC50 = 14.98±0.91 μM) was found to be comparable to the standard drug ascorbic acid. The binding modes of compounds 4a-g against the molecular target EGFR tyrosine kinase were also studied. The structure-activity relationship (SAR) was also studied. The compound 4g showed significant anticancer activity with GI50 of 28.2 μM against MCF-7 (Breast cancer cell line). The antioxidant activity of the compound, 4g was found to be comparable to the standard drug ascorbic acid, while its anticancer activity was found to be less than that of the standard drug adriamycin.

An efficient method has been developed for the synthesis of new pyrano[3,2-c] and pyrano[3,2-a]carbazole derivatives via a three-component reaction of 4-hydroxycarbazole or 2-hydroxycarbazole, isocyanides, and dialkylacetylenedicarboxylates. Noteworthy features of this protocol include mild reaction conditions, catalyst-free, high atom-economy and high yields.

Synthesize and evaluate some phenyl substituted thiazole linked 1, 2, 4-triazole derivatives as antimicrobial agents. Compounds containing 1, 2, 4-triazole moieties are widely used as antimicrobial and antifungal agents whereas thiazole is another heterocyclic ring exhibiting various pharmacological actions. It is interesting to incorporate different bioactive pharmacophores in the same molecular framework to examine cumulative effect exerted by the moiety. This hypothesis was applied in research work by having triazole and thiazole in the same molecular framework. The present work was mainly focused on synthesis of some 1, 2, 4-triazole derivatives linking with phenyl substituted thiazole nucleus and their evaluation for biological activity. The compounds (8a-8j) were synthesized as per design scheme and elucidated their structures using different spectroscopic data of IR, 1HNMR, 13CNMR & mass spectroscopy. These synthesized derivatives were evaluated for their antibacterial activity using broth dilution assay. Further, mechanism of action of test compounds was examined using protein leakage assay. All the spectral data were confirmed the synthesis of phenyl substituted thiazole linked 1, 2, 4- triazole derivatives and some of them exhibited significant antimicrobial activity. Amongst all compound 8c showed most potent activity with lowest IC50 values 180 μg/ml and 120 μg/ml against S. aureus & amp; B. cereus respectively. Whereas compound 8j demonstrated strong inhibitory activities only against negative strains P. aeruginosa and E. coli with lowest IC50 values 240 μg/mL and 200μg/mL respectively.

The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities, including inflammatory action. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure. Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant, etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have a significant anti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate it as an anti-inflammatory agent. In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a threestep reaction. The compounds were subjected to spectral analysis by Infrared, Mass, and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized derivatives were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Compounds PT-1, PT-3, PT-4, and PT-8 exhibited significant anti-inflammatory activity at 3rd hour, being 50.7%, 54.3%, 52.3%, and 57%, respectively, closer to that of the standard drug indomethacin (61.9%). From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed a docking score of -6.5 kJ/mol, compound PT-1 exhibited the highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 had a docking score of 9.4 kJ/mol for COX-2. It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors was very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

The aim of present work is one-pot catalyst free green synthesis of tetrahydropyrimidne derivatives through Biginelli condensation under ultrasonic irradiation. The chemical applications of ultrasound, "sonochemistry", has become an exciting new field of research during the past decade as it can increase reactivities by nearly a million fold. Owing to the increasing use of Green technology approach, due to its various merits over Classical methodology and as a need for sustainable Chemistry, this reaction has received renewed interest for preparing tetrahydropyrimidine (THPM) through Biginelii condensation in an environmentally thoughtful manner with improved yields. The objective of the present study is focused on developing novel Ultrasound-Assisted catalyst free one-pot synthesis of tetrahydropyrimidne derivatives through Biginelli condensation We, herein describe a highly efficient catalyst free one-pot green synthesis of tetrahydropyrimidine derivatives using Biginelli protocol under ultrasonic irradiation at 50°C. All the products were characterized by comparing their physical and spectral data with those of authentic compounds reported in the literature. A green and efficient ultrasound-assisted one-pot synthesis method for tetrahydro-yrimidine derivatives have been developed through Biginelli condensation. The technique affords up to 99% yield in only 5–20 minutes under mild heating. Each synthesized compounds were fully characterized through spectral techniques viz. IR, ¹H NMR, and Mass Spectroscopy. A green and efficient ultrasound-assisted one-pot synthesis method for tetrahy-droyrimidine derivatives have been developed through Biginelli condensation. The present sonochemistry based green chemistry approach with no additional acid catalyst produces no waste, shows a significant enhancement in reaction rates under mild ultrasound irradiation in excellent yields and therefore represents a green and enviro-economic synthetic methodology for the Biginelli condensation in comparison to conventional heating/micro-wave irradiation.