Medicinal Chemistry - Volume 18, Issue 8, 2022

Background: Pyrazole scaffolds have gained importance in drug discovery and development for various pharmacological activities like antiviral, antifungal, anticancer, antidepressant, antiinflammatory, antibacterial, etc. Additionally, the pyrazole moiety has shown potent anti-HIV activity as a core heterocycle or substituted heterocycles derivatives (mono, di, tri, tetra, and fused pyrazole derivatives). To assist the development of further potential anti-HIV agents containing pyrazole nucleus, here we have summarized pyrazole containing anti-HIV compounds that have been reported by researchers all over the world for the last two decades. Objective: The present review concentrates on an assortment of pyrazole containing compounds, particularly for potential therapeutic activity against HIV. Methods: Google Scholar, Pubmed, and SciFinder were searched databases with ‘‘pyrazol’’ keywords. Further, the year of publication and keywords ‘‘Anti-HIV’’ filter was applied to obtain relevant reported literature for anti-HIV agents containing pyrazole as a core or substituted derivatives. Results: This review article has shown the comprehensive compilation of 220 compounds containing pyrazole nucleus and possessing anti-HIV activity by sorting approximately 40 research articles from 2001 to date. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin- 3-yl)ethane-1,2-dione (13), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-fluoro-1H-pyrrolo[2,3- c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (31), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4- fluoro-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (88), 3-cyanophenoxypyrazole derivative (130), and 4-(4-chlorophenyl)-5-(4-methyl-5-((4-nitrophenyl)diazenyl)thiazol-2-yl)-3- phenyl-5,6-dihydro-4H-pyrazolo[4,3-d]isoxazole (178) were the most potent mono-, di-, tri-, tetrasubstituted, and fused pyrazole derivatives, respectively, which have shown potent anti-HIV activity among all the described derivatives as compared with standard anti-HIV drugs. Conclusion: This review article provides an overview of the potential therapeutic activity of pyrazole derivatives against HIV that will be helpful for designing pyrazole containing compounds for anti-HIV activity.

The ongoing pandemic of Covid-19 caused by SARS-CoV-2 is a major threat to global public health, drawing attention to develop new therapeutics for treatment. Much research work is focused on identifying or repurposing new small molecules to serve as potential inhibitors by interacting with viral or host-cell molecular targets and understanding the nature of the virus in the host cells. Identifying small molecules as potent inhibitors at an early stage is advantageous in developing a molecule with higher potency and then finding a lead compound for the development of drug discovery. Small molecules can show their inhibition property by targeting either the SARS-CoV-2 main protease (M^pro) enzyme, papain-like protease (PL^pro) enzyme, or helicase (Hel), or blocking the spike (S) protein angiotensin-converting enzyme 2 (ACE2) receptor. A very recent outbreak of a new variant (B.1.617.2—termed as Delta variant) of SARS-CoV-2 worldwide posed a greater challenge as it is resistant to clinically undergoing vaccine trials. Thus, the development of new drug molecules is of potential interest to combat SARS-CoV-2 disease, and for that, the fragment-based drug discovery (FBDD) approach could be one of the ways to bring out an effective solution. Two cysteine protease enzymes would be an attractive choice of target for fragment-based drug discovery to tune the molecular structure at an early stage with suitable functionality. In this short review, the recent development in small molecules as inhibitors against Covid-19 is discussed, and the opportunity for FBDD is envisioned optimistically to provide an outlook regarding Covid-19 that may pave the way in the direction of the Covid-19 drug development paradigm.

In the present-day scenario, heterocyclic derivatives have revealed the primary function of various medicinal agents precious for humanity. Out of a diverse range of heterocycles, Styrylquinolines scaffolds have been proved to play an essential role in a broad range of biological activities, including anti-HIV-1, antimicrobial, anti-inflammatory, anti-Alzheimer activity with antiproliferative effects on tumor cell lines. Due to the immense pharmacological importance, distinct synthetic methods have been executed to attain new drug entities from Styrylquinolines. Various schemes for synthesizing Styrylquinolines derivatives like one-pot, ultrasound-promoted heterogeneous acid-catalysed, microwave-assisted, solvent-free, and green synthesis were discussed in the present review. Some products of Styrylquinolines are in clinical trials, and patents are also granted for the novel synthesis of Styrylquinolines. According to the structure-activity relationship, replacement at the R-7 and R-8 positions is required for various activities. In this review, recent synthetic approaches in the medicinal chemistry of Styrylquinolines and potent Styrylquinolines derivatives based on structural activity relationships (SAR) are outlined. Moreover, their primary methods and modifications are also discussed.

Background: Chemokines are involved in several human diseases and different stages of COVID-19 infection. They play a critical role in the pathophysiology of the associated acute respiratory disease syndrome, a major complication leading to death among COVID-19 patients. In particular, CXC chemokine receptor 4 (CXCR4) was found to be highly expressed in COVID-19 patients. Methods: We herein describe a computational workflow based on combining pharmacophore modeling and QSAR analysis towards the discovery of novel CXCR4 inhibitors. Subsequent virtual screening identified two promising CXCR4 inhibitors from the National Cancer Institute (NCI) list of compounds. The most active hit showed in vitro IC50 value of 24.4 μM. Conclusion: These results proved the validity of the QSAR model and associated pharmacophore models as means to screen virtual databases for new CXCR4 inhibitors as leads for the development of new COVID-19 therapies.

Aims: The present study aimed at characterizing the impact of the presence or absence of fluorine atoms on the phenyl and benzopyran rings of 4-phenyl(thio)ureido-substituted 2,2- dimethylchromans on their ability to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells. Methods: Most compounds were found to inhibit insulin secretion and to provoke a marked myorelaxant activity. Results: The lack of a fluorine or chlorine atom at the 6-position of the 2,2-dimethylchroman core structure reduced the inhibitory activity on the pancreatic endocrine tissue. One of the most active compounds on both tissues, compound 11h (BPDZ 678), was selected for further pharmacological investigations. Conclusion: The biological data suggested that 11h mainly expressed the profile of a KATP channel opener on pancreatic β-cells, although a calcium entry blockade effect was also observed. On vascular smooth muscle cells, 11h behaved as a calcium entry blocker.

Background: In recent years, the anticancer effects of biguanide drugs have received considerable attention. However, the effective concentration of biguanide drugs to kill cancer cells is relatively high. Thus, we focus on structural modification of biguanides to obtain better antitumor candidates. A previous study in our laboratory has found that a biguanide compound containing the n-heptyl group has potent anticancer activity. However, the effect of different substituents on the benzene ringside of the biguanides on the anti-proliferative activity is unknown. Objective: A series of n-heptyl-containing biguanide derivatives whose benzene rings were modified by halogen substitution based on the intermediate derivatization method were further synthesized to find new compounds with improved antiproliferative activities. Methods: Ten n-heptyl-containing biguanide derivatives were synthesized via established chemical procedures. The activities of these derivatives were explored by MTT assay, clonogenic assay, and scratch assay. The protein levels were detected via Western blotting to explore the underlying mechanisms. Results: The optimal biguanide derivatives 10a-10c, 11d exhibited IC50 values of 2.21-9.59 μ for five human cancer cell lines, significantly better than the control drug proguanil. The results of clonogenic and scratch wound healing assays also confirmed the inhibitory effects of derivatives 10a- 10c, 11d on the proliferation and migration of human cancer cell lines. Western blot results demonstrated that one representative derivative, 10c upregulates the AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K. Conclusion: All biguanide derivatives containing n-heptyl groups are more active than proguanil, indicating that the modification of n-heptyl-containing biguanide derivatives provides a novel approach for the development of novel high efficient antitumor drugs.

Background: Breast cancer is currently the leading cause of worldwide cancer incidence exceeding lung cancer. In addition, breast cancer accounts for 1 in 4 cancer cases and 1 in 6 cancer deaths among women. Cytotoxic chemotherapy is still the main therapeutic approach for patients with metastatic breast cancer. Objective: The aim of the study was to synthesize a series of novel celecoxib analogues to evaluate their anticancer activity against the MCF-7 cell line. Methods: Our design of target compounds was based on preserving the pyrazole moiety of celecoxib attached to two phenyl rings, one of them having a polar hydrogen bonding group (sulfonamide or methoxy group). The methyl group of the second phenyl ring was replaced with chlorine or bromine atom. Finally, the trifluoromethyl group was replaced with arylidene hydrazine-1-carbonyl moiety, which is substituted either with fluoro or methoxy group, offering various electronic and lipophilic environments. These modifications were carried out to investigate their effects on the antiproliferative activity of the newly synthesized celecoxib analogues and to provide a valuable structure- activity relationship. Results: Four compounds, namely 4e-h, exhibited significant antitumor activity. Compounds 4e, 4f and 4h showed 1.2-2 folds more potent anticancer activity than celecoxib. Celecoxib analogue 4f showed the most potent anti-proliferative activity. Its anti-proliferative activity seems to associate well with its ability to inhibit BCL-2. Moreover, activation of the damage response pathway of the DNA leads to cell cycle arrest at the G2/M phase and accumulation of cells in the pre-G1 phase, indicating that cell death proceeds through an apoptotic mechanism. Compound 4f exhibited a potent pro-apoptotic effect via induction of the intrinsic mitochondrial pathway of apoptosis. This mechanistic pathway was proved by a significant increase in the expression of the tumor suppressor gene p53, elevation in Bax/BCL-2 ratio, and a significant increase in the level of active caspase-7. Furthermore, compound 4f showed moderate COX-2 inhibitory activity. Conclusion: Celecoxib analogue 4f is a promising multi-targeted lead for the design and synthesis of potent anticancer agents.