In this present research, an attempt has been made to address the influence of drug-coformer stoichiometric ratio on cocrystal design and its impact on improvement of solubility and dissolution, as well as bioavailability of poorly soluble telmisartan. The chemistry behind cocrystallization and the optimization of drug-coformer molar ratio were explored by the molecular docking approach, and theoretical were implemented practically to solve the solubility as well as bioavailability related issues of telmisartan. A new multicomponent solid form, i.e., cocrystal, was fabricated using different molar ratios of telmisartan and maleic acid, and characterized by SEM, DSC and XRD studies. The molecular docking study suggested that specific molar ratios of drug-coformer can successfully cluster with each other and form a specific geometry with favourable energy conformation to form cocrystals. Synthesized telmisartan-maleic acid cocrystals showed remarkable improvement in solubility and dissolution of telmisartan by 9.08-fold and 3.11-fold, respectively. A SEM study revealed the formation of cocrystals of telmisartan when treated with maleic acid. DSC and XRD studies also confirmed the conversion of crystalline telmisartan into its cocrystal state upon treating with maleic acid. Preclinical investigation revealed significant improvement in the efficacy of optimized cocrystals in terms of plasma drug concentration, indicating enhanced bioavailability through improved solubility as well as dissolution of telmisartan cocrystals. The present research concluded that molecular docking is an important path in selecting an appropriate stoichiometric ratio of telmisartan: maleic acid to form cocrystals and improve the solubility, dissolution, and bioavailability of poorly soluble telmisartan.

Synthesis of pharmaceutically active heterocycles is always appealing as the majority of the widely used drugs contain heterocyclic moieties as their core structure. So, the straightforward construction of heterocycles from readily available/accessible reagents is one of the prime targets of the synthetic chemists. In this context, CÀ H functionalization has emerged as an effective tool for the designing and synthesis of various heterocyclic moieties as it offers a straightforward and step-economic pathway. On the other hand, the readily available/accessible conjugated carbonyls are well-known reagents for the construction of carbocycles and heterocycles over the years. However, the employment of CÀ H functionalization of the two CÀ H bonds of the conjugated alkene in carbocycle/heterocycle synthesis was not so explored. In the last decade, much focus has been paid on the synthesis of various pharmaceutically active heterocycles through CÀ H bond functionalization of α,β-unsaturated aldehydes/ketones. These protocols have been developed through either oxida-tive coupling of conjugated carbonyls with suitable coupling partners or intramolecular CÀ H bond functionalization of conjugated carbonyls. In this review, we will discuss all the methodologies developed for the synthesis of heterocycles employing intermolecular CÀ H bond functionalization of conjugated carbonyls. The mechanistic pathways and usefulness of the methodologies will be also highlighted.

We disclose a metal-free, cascade regio- and stereoselective trifluormethyloximation, cyclization, and elimination strategy with readily available α,β-unsaturated carbonyl compounds to access a wide variety of pharmaceutically potential heteroaromatics, i.e., 4-(trifluoromethyl)isoxazoles including a trifluoromethyl analogue of an anticancer agent. The transformation requires only a couple of commercially available and cheap reagents i.e., CF3SO2Na as the trifluoromethyl source, and t BuONO as an oxidant as well as a source of N and O. Notably, 5-alkenyl-4-(trifluoromethyl)isoxazoles were further synthetically diversified to a new class of biheteroaryls, i.e., 5-(3-pyrrolyl)-4-(trifluoromethyl)isoxazoles. Mechanistic studies revealed a radical pathway for the reaction.