Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency

Abstract

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.

2,6‐Pyridinedicarboxylic Acid (PDCA) Catalyzed Improved Synthetic Approach for 1‐Amidoalkyl Naphthols, Dihydropyrimidin‐2(1H)‐ones and Bis‐indoles

“…On the other hand, the high loading of catalyst did not show any improvement in yield and time for conversion. (Table 1 entry 21,22). Also, high catalyst loading leads to the formation of undesired products (observed on TLC).…”

“…1-Amidoalkyl-2-naphthol, DHPMs and bis-indole skeletons are present in several pharmaceutical drug intermediates. Amidoalkyl naphthol has gained strong interest by its potent pharmaceutical properties such as adrenoceptor blocking, [13] antihypertensive, [13] and Ca 2 + channel blocking deeds.. [13] (Figure 1) Amidoalkyl naphthol was also used in the synthesis of 1,3-oxazines, which have numerous biological actions including antirheumatic, [14] antibiotic, [15] antitumor, [16] antipsychotic, [17] antihypertensive, [18] analgesic, [19] antianginal, [20] anticonvulsant, [21] antimalarial [22] and antibacterial [21] properties. 1-Amidoalkyl-2-naphthols can be effortlessly transformed into 1-aminoalkyl-2-naphthols derivatives by an amide hydrolysis reaction which exhibits depressor [23] and bradycardia effects in humans.…”

Oxadiazole: A highly versatile scaffold in drug discovery

“…[ 7–14 ] The other heterocycles like pyrimidine, furan, pyrrole, indole, oxadiazole, benzoxazole, azetidine, thiophene, coumarin, benzofuran, pyrazole, quinoline oxazole, quinazoline, pyrimidine, thiazole, quinoline, pyrazole, and isoxazole also possess various pharmacological activities. [ 8,15–30 ]…”

“…[7][8][9][10][11][12][13][14] The other heterocycles like pyrimidine, furan, pyrrole, indole, oxadiazole, benzoxazole, azetidine, thiophene, coumarin, benzofuran, pyrazole, quinoline oxazole, quinazoline, pyrimidine, thiazole, quinoline, pyrazole, and isoxazole also possess various pharmacological activities. [8,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] The Food and Drug Administration (FDA)-approved drugs in recent years contain biologically active heterocycles in their structures. The drugs like remdesivir (broad-spectrum antiviral drug), [31] avaprinitib (an antitumor drug), [32] pematinib (an anticancer drug used to treat cholangiocarcinoma), [33] remimazolam (sedative drug), [34] and oliceradine (pain medication) [35] approved in 2020 (Figure 1).…”

Synthesis of new coumarin[1,3]oxazine derivatives of 7‐hydroxy‐6‐isobornyl‐4‐methylcoumarin and their antioxidant activity

“…The interest of researchers to the chemistry of 1,3‐oxazine derivatives is constantly increasing, which is associated with a wide range of biological activities, such as anticancer, anti‐inflammatory, antiviral, antifungal, and antiparasitic (Carramiñana et al, 2020; Chanu et al, 2020; Mbaba et al, 2021; Nongrum et al, 2019; Zhang et al, 2016, 2017). A detailed review on the synthesis of oxazine derivatives and their pharmaceutical and biological activities was recently published (Zinad et al, 2020).…”