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An overview on various transition metal-catalyzed reactions of chloroquinoxalines and in vitro , in silico biological studies including SAR of the products along with the current state-of-the-art as well as future directions are presented. [Display omitted] • Chloroquinoxalines participated in a range of transition metal-catalyzed reactions. • Generally, Sonogashira coupling predominated over other coupling reactions. • This allowed easy access to quinoxaline derivatives of biological and other interest. • In vitro , in silico studies including SAR of quinoxaline derivatives are presented. • Quinoxaline-based NCEs, hits or leads identified so far are mostly covered. The importance of the quinoxaline framework is exemplified by its presence in the well-known drugs such as varenicline, brimonidine, quinacillin, etc. In the past few years, preparation of a variety of organic compounds containing the quinoxaline framework has been reported by several research groups. The chloroquinoxalines were successfully used as substrates in many of these synthetic approaches due to their easy availability along with the reactivity especially towards a diverse range of metal and transition metal-catalyzed transformations including Sonogashira, Suzuki, Heck type of cross-coupling reactions. The transition metals e.g., Pd, Cu, Fe and Nb catalysts played a key role in these transformations for the construction of various C X (e.g., C C, C N, C O, C S, C P, C Se, etc) bonds. These approaches can be classified based on the catalyst employed, type of the reaction performed and nature of C X bond formation during the reaction. Several of these resultant quinoxaline derivatives have shown diverse biological activities which include apoptosis inducing activities, SIRT1 inhibition, inhibition of luciferace enzyme, antibacterial and antifungal activities, cytotoxicity towards cancer cells, inhibition of PDE4 (phosphodiesterase 4), potential uses against COVID-19, etc. Notably, a review article covering the literature based on transition metal-catalyzed reactions of chloroquinoxalines at the same time summarizing the relevant biological activities of resultant products is rather uncommon. Therefore, an attempt is made in the current review article to summarize (i) the recent advances noted in the transition metal-catalyzed reactions of chloroquinoxalines (ii) with the relevant mechanistic discussions (iii) along with the in vitro , and in silico biological studies (wherever reported) (iv) including Structure-Activity Relationship (SAR) within the particular series of the products reported between 2010 and 2022. [ABSTRACT FROM AUTHOR]

[Display omitted] • 3-(1-Hydroxycycloalkyl)isoquinolin-1-ones emerged as potential PAAM of 5-HT 2C R. • These compounds and regioisomeric isoindolin-1-ones were synthesized via Cu-catalysis. • 4i showed PAAM activity for 5-HT 2C R (EC 50 = 1 nM) and selectivity over 2A and 2B. • 4i also showed an acceptable PK and decrease in food intake. • In silico, in vitro and in vivo studies suggested 4i is a promising probe or hit. Efforts have been devoted for the discovery and development of positive allosteric modulators (PAMs) of 5-HT 2C R because of their potential advantages over the orthosteric agonist like Lorcaserin that was withdrawn from the market. On the other hand, pursuing a positive ago-allosteric modulator (PAAM) is considered as beneficial particularly when an agonist is not capable of affecting the potency of the endogenous agonist sufficiently. In search of a suitable PAAM of 5-HT 2C R we adopted an in silico based approach that indicated the potential of the 3-(1-hydroxycycloalkyl) substituted isoquinolin-1-one derivatives against the 5-HT 2C R as majority of these molecules interacted with the site other than that of Lorcaserin with superior docking scores. These compounds along with the regioisomeric 3-methyleneisoindolin-1-one derivatives were prepared via the Cu(OAc) 2 catalyzed coupling of 2-iodobenzamide with 1-ethynylcycloalkanol under ultrasound irradiation. According to the in vitro studies, most of these compounds were not only found to be potent and selective agonists but also emerged as PAAM of 5-HT 2C R whereas Lorcaserin did not show PAAM activities. According to the SAR study the isoquinolin-1(2 H)-ones appeared as better PAAM than isoindolin-1-ones whereas the presence of hydroxyl group appeared to be crucial for the activity. With the potent PAAM activity for 5-HT 2C R (EC 50 = 1 nM) and 107 and 86-fold selectivity towards 5-HT 2C over 5-HT 2A and 5-HT 2B the compound 4i was identified as a hit molecule. The compound showed good stability in male BALB/c mice brain homogenate (∼85 % remaining after 2 h), moderate stability in the presence of rat liver microsomes (42 % remaining after 1 h) and acceptable PK properties with fast reaching in the brain maintaining ∼ 1:1 brain/plasma concentration ratio. The compound at a dose of 50 mg/kg exhibited decreased trend in the food intake starting from day 3 in S.D. rats, which reached significant by 5th day, and the effect was comparable to Lorcaserin (10 mg/kg) on day 5. Thus, being the first example of PAAM of 5-HT 2C R the compound 4i is of further medicinal interest. [ABSTRACT FROM AUTHOR]

[Display omitted] • New class of isoquinolin-1(2 H)-ones were designed and explored as inhibitors of PDE4. • For the first time a CuCl 2 -catalyzed approach was developed for their synthesis. • This inexpensive, faster, ligand free approach proceeds with high chemo/regioselectivity. • Compound 3c , 3k and 3s showed good inhibition of PDE4B and TNF-α in vitro. • 3k showed good interactions and selectivity for PDE4B over PDE4D in silico. • With favorable ADME and safety prediction in silico 3k represents a novel hit. In spite of possessing a wide range of pharmacological properties the anti-inflammatory activities of isoquinolin-1(2 H)-ones were rarely known or explored earlier. PDE4 inhibitors on the other hand in addition to their usefulness in treating inflammatory diseases have been suggested to attenuate the cytokine storm in COVID-19 especially TNF-α. In our effort, a new class of isoquinolin-1(2 H)-ones derivatives containing an aminosulfonyl moiety were designed and explored as potential inhibitors of PDE4. Accordingly, for the first time a CuCl 2 -catalyzed inexpensive, faster and ligand/additive free approach has been developed for the synthesis of these predesigned isoquinolin-1(2 H)-one derivatives via the coupling–cyclization strategy. Thus, the CuCl 2 -catalyzed reaction of 2-iodobenzamides with appropriate terminal alkynes proceeded with high chemo and regioselectivity affording the desired compounds in 77–84% yield within 1–1.5 h. The methodology also afforded simpler isoquinolin-1(2 H)-ones devoid of aminosulfonyl moiety showing a broader generality and scope of this approach. Several of the synthesized compounds especially 3c , 3k and 3s showed impressive inhibition (83–90%) of PDE4B when tested at 10 µM in vitro whereas compounds devoid of aminosulfonyl moiety was found to be less active. In spite of high inhibition showed at 10 µM these compounds did not show proper concertation dependent inhibition below 1 µM that was reflected in their IC 50 values e.g. 2.43 ± 0.32, 3.26 ± 0.24 and 3.63 ± 0.80 µM for 3k , 3o and 3s respectively. The anti-inflammatory potential of these compounds was indicated by their TNF-α inhibition (60–50% at 10 µM). The in silico docking studies of these molecules suggested good interactions with PDE4B and selective inhibition of PDE4B by 3k over PDE4D that was supported by in vitro assay results. These observations together with the favorable ADME and safety predicted for 3k in silico not only suggested 3k as an interesting hit molecule for further studies but also reveal the first example of isoquinolin-1(2 H)-one based inhibitor of PDE4B. [ABSTRACT FROM AUTHOR]