Recent developments in the synthesis of hybrid antimalarial drug discovery.

In this 21st century, Malaria remains a global burden and causes massive economic trouble to disease-endemic nations. The control and eradication of malaria is a major challenge that requires an urgent need to develop novel antimalarial drugs. To overcome the aforementioned situation, several researchers have given significant effort to develop hybrid antimalarial agents in the search for new antimalarial drugs. Hence, we have summarized those developments of hybrid antimalarial agents from 2017 to till date. This review illustrates the current progress in the recent synthesis of hybrid antimalarial agents along with focusing on their antimalarial evaluation to find the most potent hybrids. This present mini-review will also be useful for the scientific community for the development of new antimalarial drugs to eradicate malaria.

Recent advances on synthesis of C-glycosides.

In recent years, C-glycosides have emerged as significant building blocks for many naturally occurring alkaloids and pharmaceutically active drug molecules. Therefore, significant efforts have been devoted to the construction of structurally important C-glycosidic linkages in carbohydrate compounds. Herein, we have summarized the recent developments of diverse synthesis of C-glycoside core between the time period from 2019 to 2022 focusing on different catalytic strategies, such as (i) transition-metal, and (ii) metal-free catalytic approaches. Further, the transition metal catalyzed C-glycosylations have been categorized into four sub classes: (a) metal based C-H activation, (b) cross-coupling reaction, (c) glycosyl radical intermediate-based process, and (d) Others.

Base mediated green synthesis of enantiopure 2-C-spiro-glycosyl-3-nitrochromenes.

A novel green synthetic methodology has been developed to obtain enantiopure (2S)-2-C-spiro-glycosyl-3-nitrochromenes following the oxa-Michael-aldol condensation reaction of sugar derived 3-C-vinyl nitro olefins with substituted salicylaldehydes using Et3N as a base under neat conditions at rt-40 °C. The stereochemistry of the product is confirmed by a single crystal X-ray study. Several advantages are associated with this protocol such as cost effectiveness, easy accessibility, short reaction time, high yields, wide substrate scope and high enantiopurity.

Diastereoselective synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels-Alder reaction and in vitro anticancer studies.

The development of concise methods for the synthesis of small functionalised spirocyclic molecules is important in the search of new bioactive molecules. To contribute this, here we represent a diastereoselective oxa-hetero-Diels-Alder reaction for the synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives and studied their in vitro anticancer activities. Using previously less explored cyclic ketone i.e. indane-1,3-dione and 3-vinyl-2H-chromene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between "drug-like" molecules and natural products. Various spiro indanone fused pyrano[3,2-c]chromene derivatives were synthesized regiospecifically bearing a quaternary stereocenter in high yields (up to 85%) with excellent diastereoselectivity in toluene using 4 Å MS as additive under reflux condition at 120 °C. In vitro cytotoxic studies of these compounds against MCF-7 (breast cancer), HCT-116 (colon cancer), H-357 (oral cancer), MD-MB-231(Breast cancer) cell lines were evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide} assay in vitro. The screening results revealed that many of the compounds are showing moderate to high levels of anticancer activities against the tested cancer cell lines and some displayed potent inhibitory activities in comparison to the commercial anticancer drug 5-fluorouracil (5-FU). Among the series, compound 3'c showed most potent cytotoxicity (15.0-27.5 µM) in three cancer cell lines (MCF-7, HCT-116 and MD-MB-231).

14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) surrogates: carboxylate modifications.

The cytochrome P450 eicosanoid 14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a powerful endogenous autacoid that has been ascribed an impressive array of physiologic functions including regulation of blood pressure. Because 14,15-EET is chemically and metabolically labile, structurally related surrogates containing epoxide bioisosteres were introduced and have become useful in vitro pharmacologic tools but are not suitable for in vivo applications. A new generation of EET mimics incorporating modifications to the carboxylate were prepared and evaluated for vasorelaxation and inhibition of soluble epoxide hydrolase (sEH). Tetrazole 19 (ED50 0.18 µM) and oxadiazole-5-thione 25 (ED50 0.36 µM) were 12- and 6-fold more potent, respectively, than 14,15-EET as vasorelaxants; on the other hand, their ability to block sEH differed substantially, i.e., 11 vs >500 nM. These data will expedite the development of potent and specific in vivo drug candidates.

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines.

Enantioselective organocatalysis has become a field of central importance within asymmetric chemical synthesis and appears to be efficient approach toward the construction of complex chiral molecules from simple achiral materials in one-pot transformations under mild conditions with high stereocontrol. This review addresses the most significant synthetic methods reported on chiral-amine-catalyzed tandem Michael conjugate addition of heteroatom-centered nucleophiles to α,ß-unsaturated compounds followed by cyclization reactions for the enantioselective construction of functionalized chiral chromenes, thiochromenes and 1,2-dihydroquinolines in optically enriched forms found in a myriad of bioactive natural products and synthetic compounds.

Design and Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazole Containing Retinoids from a Retinoic Acid Receptor Agonist.

We previously synthesized novel retinoid libraries, and after screening for bioactivity found one compound BT10 that functions as a specific agonist for retinoic acid receptors. This lead compound was further derivatized using SAR and LRD to obtain 3,5-disubstituted-1,2,4-oxadiazole-containing retinoids. The new oxadiazole (amide bioisosters)-containing retinoids (compounds 1, 2, 3, 4, 5, and 6) were synthesized in 42-65% yield by reacting with (E)-4-((3-ethyl,2-4,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid and phenyl substituted amidoxime in DMF using CDI as the coupling reagent. The biological activities of the synthesized compounds are currently being evaluated.

Synthesis of function-oriented 2-phenyl-2H-chromene derivatives using L-pipecolinic acid and substituted guanidine organocatalysts.

Organocatalytic domino oxa-Michael/aldol reactions between salicylaldehyde with electron deficient olefins are presented. We screened guanidine, 1,1,3,3-tetramethylguanidine (TMG) and L-pipecolinic acid as organocatalysts for this transformation. 3-Substituted 2-phenyl-2H-chromene derivatives are synthesized with high yields and with poor enantioselectivity (5-17% ee) using L-pipecolinic acid while TMG works well with cinnamaldehyde without using co-catalyst. These 3-substituted-2-phenyl-2H-chromene derivatives are further derivatized to synthesize triazole and biotin-containing chromene derivatives, to facilitate purification of protein targets.