BACKGROUND:There are eighteen members of the Poly (ADP-ribose) polymerases (PARPs) family, which oversees various cellular processes such as maintaining the integrity of the genome, regulating transcription, cell cycle progression, initiating the DNA damage response, and apoptosis. PARP1 is an essential member of the PARP family and plays a crucial role in repairing single-strand breaks in eukaryotic cells through a process called BER (base excision repair). It is the most extensively studied and commonly found member of this family. AREA COVERED:This article discusses the advancements in developing PARP inhibitors for human cancers. It covers the discovery of new PARP1 inhibitors with chemical classifications that selectively target multiple areas using cancer models in vitro and in vivo and evaluate them critically. The focus is on patents that have been published from 2017 to 2023, except tankyrase inhibitors. EXPERT OPINION:PARP1 inhibitors were developed by various companies and academic groups from the 1990s to enhance the effectiveness of chemo and radiotherapy. However, their progress was hindered due to their severe toxicity when combined with these treatments. Therefore, on finding PARP1 inhibitors that can amplify the ability of chemotherapy agents to kill tumors while causing minimal toxicity, these substances can either be used alone as part of the synthetic lethality approach or in conjunction with radiotherapy or chemotherapy, resulting in a mutually beneficial outcome.

BACKGROUND:v-RAF murine sarcoma viral homolog B1 (BRAF) is one of the most frequently mutated kinases in human cancers. BRAF exhibits three classes of mutations: Class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). METHODS:In this paper, the protein-ligand interaction site of all three mutants: BRAF monomer, BRAF homodimer BRAF2:14-3-32, and BRAF heterodimer BRAF:14-3-32:MEK (Mitogen extracellular Kinase) has been discussed. FDA-approved drugs still have limitations against all three classes of mutants, especially against the second and third classes. Using the DesPot grid model, 1114 new compounds were designed. Using virtual screening, the three PDB Ids 4XV2 for monomers, 7MFF for homodimers, and 4MNE for heterodimers were used for 1114 newly designed compounds. RESULTS:Dabrafenib, encorafenib, sorafenib and vemurafenib were included as standard drugs. The top 10 hit molecules were identified for each protein. Additional binding studies were performed using molecular docking studies on the protein-ligand site of each PDB identifier. Absorption, distribution, metabolism, excretion (ADME) and toxicity studies were also performed. CONCLUSION:It was identified that top-hit molecules had better binding and interaction activity than standard in all three classes of mutants.

BackgroundMany infectious bacteria have changed throughout time and there are alarmingly large number of antibiotic resistant species that can withstand the inhibitory impact of these treatments., Plants are new sources of antibacterial agents hence there is a need to determine and evaluate the antioxidant activity, antibacterial properties of medicinal plantsObjectiveThe present study focuses on qualitative, quantitative phytochemical analysis, antioxidant, and antimicrobial evaluation of leaves’ extracts of Prunus cerasoides Buch. -Ham. ex D. Don.Materials and methodsThe Antioxidant activity of leaves extracts of Prunus cerasoides Buch. -Ham. ex D.Don was determined by DPPH method. Antibacterial activity was determined by serial dilution method. Further docking interactions were investigated using Maestro 12.7 (Schrodinger 2021) and ADME by using QikProp tool of Schrodingers 2021.ResultsThe leaves’ extracts of Prunus cerasoides Buch. -Ham. ex D.Don showed potent antioxidant and antibacterial activities. Methanol extract was found to be the most active against all the four strains of bacteria and showed MIC value (3.125μg/mL) against both E. coli and S. aureus. Ethyl acetate and methanol extracts had the highest radical scavenging activity. Further molecular docking and ADME studies for phytoconstituents of Prunus cerasoides Buch. -Ham. ex D. Don. using different bacterial protein targets of reported phytoconstituents of Prunus cerasoides Buch. -Ham. ex D. Don. and found that emodin, amygdalin and aromadendrin were the phytoconstituents having good docking score and drug likeliness properties.ConclusionsThe leaves extracts of Prunus cerasoides Buch. -Ham. ex D.Don showed potent free radical scavenging property as well as antibacterial activity.

MEK mutations are more common in various human malignancies, such as pancreatic cancer (70-90%), mock melanoma (50%), liver cancer (20-40%), colorectal cancer (25-35%), melanoma (15-20%), non-small cell lung cancer (10-20%) and basal breast cancer (1-5%). Considering the significance of MEK mutations in diverse cancer types, the rational design of the proposed compounds relies on the structural resemblance to FDA-approved MEK inhibitors like selumetinib and binimetinib. The compound under design features distinct substitutions at the benzimidazole moiety, specifically at positions 2 and 3, akin to the FDA-approved drugs, albeit differing in positions 5 and 6. Subsequent structural refinement was guided by key elements including the DFG motif, hydrophobic pocket and catalytic loop of the MEK protein. A set of 15 diverse diaryl benzimidazole derivatives (S1-S15) were synthesized via a one-pot approach and characterized through spectroscopic techniques, including MASS, IR, 1H NMR and 13C NMR. In vitro anticancer activities of all the synthesized compounds were evaluated against four cancer cell lines, A375, HT -29, A431 and HFF, along with the standard drug trametinib. Molecular docking was performed for all synthesized compounds (S1-15), followed by 950 ns molecular dynamics simulation studies for the promising compounds S1, S5 and S15. The stability of these complexes was assessed by calculating the root-mean-square deviation, solvent accessible surface area and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Based on the biological and computational results, S15 was the most potent compound and S1 and S5 are comparable to the standard drug trametinib.Communicated by Ramaswamy H. Sarma.

Diabetes mellitus is a serious global health concern. In this research, flavonoids and polyphenolic compounds from the Momordica charantia were searched for the potential inhibitor against dipeptidyl peptidase IV inhibitor through the in-silico techniques. First, we screened out selected compounds based on molecular docking binding score and those with good binding affinity are selected for the further molecular dynamics study and Absorption, Distribution, metabolism, Extraction (ADME). Molecular docking study revealed four phytoconstituents as potential compounds such as quercetin, catechin, naringenin and epicatechin. Further, RMSD and RMSF study shows quercetin has stable configuration than catechin. Drug likeness profile shows all selected candidate follow the Lipinski’s rule and Vaber rule. Based on computation study from the Momordica charantia plant quercetin and catechin are the highly potential compound. These compounds have the highest molecular docking score, good drug-likeness profile and stable RMSD and RMSF plot.

Semisynthetic phytochemicals in cancer treatment.

BACKGROUND:Cancer is a leading threat to humankind, accounting for nearly one million deaths in 2018, and the expected number of cancer-related deaths in 2040 is more than 16 million. The most common causes of cancer deaths are lung, colorectal, stomach, liver and breast cancer, while the highest number of new cancer cases belong to lung, breast, colorectal, prostate, stomach and liver cancer. INTRODUCTION:PARP-1 is an enzyme that plays an important role in DNA repair, cell propagation/survival and death due to its influence on numerous biological processes. Quinazolinones represent an important scaffold in medicinal chemistry and have a broad spectrum of biological activities. METHODS:In this study, we have synthesized quinazolinones by reaction of 2-aminobenzamide and substituted aldehydes. Molecular docking studies of synthesized compounds were performed for their PARP-1 binding affinities using Schrodinger 2016 software. In silico ADME studies were also performed for the synthesized compounds using the QikProp tool of Schrodinger software. RESULTS:Results of molecular docking studies indicated that synthesized quinazolinones had a good affinity towards active site of PARP-1 and compound 4 had the best docking score (-10.343). Results of ADME studies indicated the drug-like properties of synthesized compounds, which make them suitable drug candidates. CONCLUSION:All the synthesized compounds have a better docking score than niraparib (-9.05). Further, the synthesized compounds have a favorable ADME profile. Therefore, they may serve as important leads in discovering PARP-1 inhibitors.

AIM:Design, synthesis and molecular docking studies of quinoline/naphthalene containing pyrazoline derivatives as PI3K inhibitors.BACKGROUND:Phosphatidylinositol 3-kinases (PI3Ks) belong to the family of enzymes, which are associated with various cellular functions such as cell growth, proliferation, differentiation etc. Overexpression or any changes in these functions may result in various abnormalities, which in turn cause cancer.OBJECTIVES:To perform synthesis and molecular docking studies of quinoline/naphthalene containing pyrazoline derivatives as PI3K inhibitors.METHODS:2-Chloroquinoline-3-carbaldehyde was synthesized by a reaction of acetanilide and POCl3. The latter was reacted with substituted acetophenones to synthesize chalcones, which were reacted with substituted phenyl hydrazines to yield pyrazoline derivatives (Series I). Similarly, pchloro benzaldehyde was reacted with 2-acetonapthone to yield chalcone with substituted phenyl hydrazines to yield pyrazoline derivatives (Series II).RESULTS:The synthetic compounds were subjected to molecular modelling experiments using Schrodinger 2016 software and evaluated in silico for their PI3K binding affinities. All the compounds had better docking scores than AMG-319 (-4.36 Kcal/mol) and comparable docking scores with PI-103 (-6.83 Kcal/mol).CONCLUSION:Compounds 5 and 3 had the best docking scores (-7.85 and -7.17 Kcal/mol, respectively). The synthesized compounds have better docking scores than the reference drug AMG-319. As a result, they might be used as lead molecules in investigating PI3K inhibitors.

Natural Products continue to be the purest source of physiologically active molecules employed in the identification of possible lead compounds in the drug discovery process. Acanthaceae is a big plant family with around 2500 species, found primarily in subtropical and tropical regions, as well as the Mediterranean, Australia, and the United States. Several species of the Acanthaceae family have been used traditionally to treat a variety of diseases, including gastrointestinal and cardiovascular ailments, etc. Ruellia tuberosa commonly known as "Mexican Bluebell" is a perennial herb that originated in Central America and has spread to some countries in the Southern tropics and Southeast Asia. It has been utilized as a traditional Rasayana plant from ancient times. R. tuberosa extracts and phytochemicals showed potent bioactivities, such as anticancer, anti-inflammatory, wound healing, antifungal, antimicrobial, anti-diabetic, hypoglycemic, hypolipidemic, gastro-protective, and anthelminthic activities. Chemical analyses have unveiled a range of bioactive constituents within the plant, including alkaloids, flavonoids, saponins, and phenolic compounds, suggestive of its therapeutic potential. Collectively, this review provides an overview of R. tuberosa, encompassing its traditional uses, ethnomedicinal importance, phytochemistry, pharmacological properties, and toxicity.

Nano-emulsions offer controlled drug release, increased drug solubility, and improved pharmacokinetic and pharmacodynamic profile of drugs. Additionally, nano-emulsions display great stability in almost all cancer models and may deposit into pathological areas, having defective vasculatures. Various researchers have studied multifunctional nano-emulsions in different areas, mainly for treating various cancers such as prostate, ovarian, leukemia, breast, melanoma, lung, and colon etc. Nano-emulsions slow down the growth of cancer, exhibit minimal damage to normal cells, and restrict cancer cells from spreading. In this article, we have covered a detailed overview of a nano-emulsion system, its advantages, and limitations along with its role in the treatment of various cancers including colon, prostate, ovarian, leukemia, breast, melanoma, and lung cancer. Further, the challenges and prospects of nano-emulsions as drug delivery systems have also been discussed.

Genus Prunus comprising around 430 species is a vast important genus of family Rosaceae, subfamily amygdalaoidae. Among all 430 species, around 19 important species are commonly found in Indian subcontinent due to their broad nutritional and economic importance. Some most common species of genus Prunus are Prunus amygdalus, Prunus persica, Prunus armeniaca, Prunus avium, Prunus cerasus, Prunus cerasoides, Prunus domestica, Prunus mahaleb , etc. A newly introduced species of Prunus i.e Prunus sunhangii is recently discovered which is morphologically very similar to Prunus cerasoides . Plants of Prunus species are short to medium-sized deciduous trees mainly found in the northern hemisphere. In India and its subcontinent, it extends from the Himalayas to Sikkim, Meghalaya, Bhutan, Myanmar etc . Different Prunus species have been extensively studied for their morphological, microscopic, pharmacological and phytoconstituents characteristics. Total phenolic content of Prunus species explains the presence of phenols in high quantity and pharmacological activity due to phenols. Phytochemical screening of species of genus Prunus shows the presence of wide phytoconstituents which contributes in their pharmacological significance and reveals the therapeutic potential and traditional medicinal significance of this genus. Genus Prunus showed a potent antioxidant activity analyzed by 1,1-diphenyl-2picryl-hydrazyl radical assay. Plant species belonging to the genus Prunus is widely used traditionally for the treatment of various disorders. Some specific Prunus species possess potent anticancer, anti-inflammatory, hypoglycemic etc. activity which makes the genus more interesting for further research and findings. This review is an attempt to summarize the comprehensive study of Prunus species from its distribution, morphological characters to phytoconstituents, and pharmacological activity.

Background & Objective: Christopher A. Lipinski, in 1997, formulated Lipinski’s rule of five for drug-likeness prediction of potent molecules. It states that molecular weight (less than 500 Daltons), octanol/water partition coefficient (not exceeding more than 5), hydrogen bond acceptor (no more than 10), and hydrogen bond donor (no more than 5) are important for good oral bioavailability. Many drugs among various important classes such as antibiotics, anti-cancer, HIV and HCV protease inhibitors, immunosuppressants, cardiovascular, antifungal, and other miscellaneous classes are approved by FDA or other drug regulatory authorities as clinical use lie beyond the rule of five. In this review, beyond the rule of 5 drugs belonging to these classes (which are either currently approved or under clinical study) are explored and their ADME properties are analyzed. Methods: Data of 73 beyond the rule of 5 drugs, belonging to various classes, were collected and their ADME properties were calculated using the Qikprop prediction program of maestro 12.9 module of Schrodinger software. Result: Out of 73 drugs, 4 had at least 1 Rule of 5 (Ro5) violation, 16 had at least 2, 31 had at least 3 out of which 22 drugs had 4, Ro5 violations. Conclusion: Drugs not obeying the rule of five may also serve as good clinical candidates and potential candidates should not be discarded only on the basis of this rule.

Colorectal cancer (CRC) is the second most common cause of cancer-related deaths and the third most common cancer worldwide. Because of its importance in DNA biosynthesis, thymidylate synthase (TS) has gathered attention as a promising target for cancer therapy. Herein, we have designed and synthesized 12 novel 5-(N-Benzyl indol-3-yl) pyrido[2, 3-d] pyrimidine based derivatives and assessed their anticancer activity against HCT 116, MCF-7, Hep G2, and PC-3 cell lines. For compounds 5 a and 5 f TS inhibitory activity was also performed along with in silico studies. Further, all the synthesized compounds exhibited anticancer activity, but particularly, compounds 5 a and 5 f were showed excellent anticancer activity having IC50 values of 1.09 +/- 0.61, 5.54 +/- 0.81, 6.44 +/- 0.91, and 5.12 +/- 0.65 mu M and 1.03 &+/- 0.96, 3.09 +/- 0.52, 4.12 +/- 0.59, and 7.06 +/- 0.60 mu M respectively with control Raltitrexed (IC50 1.02 +/- 0.51, 1.88 &+/- 0.61, 1.30 +/- 0.89, and 2.09 +/- 0.67 mu M respectively) and hTS inhibitory activity with IC50 of 18.91 +/- 1.09 and 16.19 +/- 0.96 nM with control Raltitrexed (IC50 12.25 +/- 1.21 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 5 a and 5 f to the catalytic site of TS. Additionally, ADME characteristics were also in the acceptable range for these compounds. Based on the anticancer activity, SAR was also performed for lead optimization.

Worldwide, colorectal cancer (CRC) is the third most common type of cancer and the second most common cause of cancer-related deaths. Thymidylate synthase (TS) is a crucial component of DNA biosynthesis and has drawn interest as an essential target for cancer treatment. In the current work, we have designed and synthesized twenty-eight new diaryl-based pyrido[2,3-d]pyrimidine/alkyl-substituted pyrido[2,3-d]pyrimidine derivatives and evaluated their anticancer activity against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines cell lines. Additionally, we have carried out TS inhibitory activity and in silico studies for compounds 1n and 2j. All the synthesized compounds exhibited good anticancer activity, but among them, compounds 1n and 2j showed excellent anticancer activity, having IC50 values of 1.98 ± 0.69, 2.18 ± 0.93, 4.04 ± 1.06, and 4.18 ± 1.87 µM; and 1.48 ± 0.86, 3.18 ± 0.79, 3.44 ± 1.51, and 5.18 ± 1.85 µM, against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines respectively with control raltitrexed (IC50 1.07 ± 1.08, 1.98 ± 0.72, 1.34 ± 1.0, and 3.09 ± 0.96 µM, respectively) and hTS inhibitory activity with IC50 values of 20.47 ± 1.09 and 13.48 ± 0.96 nM with control raltitrexed (IC50 14.95 ± 1.01 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 1n and 2j to the catalytic site of TS with docking scores of -10.6 and − 9.5 kcal/mol, respectively, with reference raltitrexed (-9.4 kcal/mol). Additionally, the assessment of physicochemical, biochemical, structural, and toxicological characteristics were also in the acceptable range for these compounds. Based on the anticancer activity of compounds, SAR was also performed for lead optimization.

Tuberculosis (TB) is the major cause of mortality around the world and one of the most common diseases linked to AIDS. Due to the emergence of multi-drug resistance, extensive drug resistance, and total drug resistance strains, TB has become a difficult disease to treat. Isoxazole scaffold shows a wide range of biological activities, including anticancer, antibacterial, antitubercular, antiviral, and anti-inflammatory activities etc. Several isoxazole derivatives have been produced and few of them have shown comparable anti-tubercular activity with standard drugs. In this review, we have focused on reported isoxazole derivatives having anti-tubercular activity and summarized their structure-activity relationship.

The present study was designed to appraise the photoprotective, antioxidant, and antibacterial bioactivities of Ruellia tuberosa leaves extracts (RtPE, RtChl, RtEA, RtAc, RtMe, and RtHMe). The results showed that, RtHMe extracts of R. tuberosa was rich in total phenolic content, i.e., 1.60mgGAE/g dry extract, while highest total flavonoid content was found in RtAc extract, i.e., 0.40mgQE/g. RtMe showed effective antioxidant activity (%RSA: 58.16) at the concentration of 120 mu L. RtMe, RtEA and RtHMe exhibited effective invitro antibacterial activity against Gram-negative bacteria (E. coli). In silico docking studies revealed that paucifloside (-11.743kcal/mol), indole-3-carboxaldehyde (-7.519kcal/mol), nuomioside (-7.275kcal/mol), isocassifolioside (-6.992kcal/mol) showed best docking score against PDB ID 2EX8 [penicillin binding protein 4 (dacB) from Escherichia coli, complexed with penicillin-G], PDB ID 6CQA (E. coli dihydrofolate reductase protein complexed with inhibitor AMPQD), PDB ID 2Y2I [Penicillin-binding protein 1B in complex with an alkyl boronate (ZA3)] and PDB ID 2OLV (from S. aureus), respectively. Docked phytochemicals also showed good drug likeness properties.

Dihydropyrimidinones (DHPMs) are characterized by their multifunctionalized scaffold with a pyrimidine moiety that exhibits diverse biological activities, especially anticancer activity. Malignant clonal expansion of blood-forming cells is referred to as blood cancer. Colorectal cancer (CRC) appears within the colon or another bodily area. There were 9,958,133 fatalities and 19,292,789 new cases of 36 cancers globally in 2020. In this, 1,148,515 cases and 576,858 deaths belong to colon cancer, whereas 474,519 cases and 311,594 deaths belong to leukemia. Different blood cancer cell lines, such as MOLT-4, HL-60, CCRF-CEMT, K-562, U937, MOLT-4, RPMI-8226, THP-1, and SR, as well as colon cancer/CRC cell lines, HCT-116, HCT-15, Colo205, HCC-2998, HCT-116, HT-29, KM-12, and SW-620, have been used to evaluate in vitro anticancer activity of DHPM derivatives. DHPM derivatives demonstrated notable effectiveness against blood and colon/colorectal cancers and may prove important building blocks in the development of novel anticancer agents.

Metal complexes in cancer therapy have attracted much interest mainly because metals exhibit unique characteristics, such as redox activity, metal-ligand interaction, structure and bonding, Lewis acid properties etc. In 1965, Barnett Rosenberg serendipitously discovered the metal-based compound cisplatin, an outstanding breakthrough in the history of metal-based anticancer complexes and led to a new area of anticancer drug discovery. Many metal-based compounds have been studied for their potential anticancer properties. Some of these compounds have FDA approval for clinical use, while others are now undergoing clinical trials for cancer therapy and detection. In the present study, we have highlighted the primary mode of action of metallic complexes and all FDA-approved/under clinical trial drugs with reference to cancer treatment. This review also focuses on recent progress on metal-based complexes such as platinum, ruthenium, iron, etc. with potential anticancer activities.

PI3K is an important anticancer target as it controls cellular functions such as growth, transformation, proliferation, motility and differentiation. Plasma cell cancer (multiple myeloma) occurs more than 10% among all haematological malignancies and accounts for 2% of all cancer-related deaths each year, it is mainly regulated by PI3K/AKT signaling cascade. Quinazoline derivatives have been reported as promising PI3K inhibitors. Lapatinib, afatinib, gefitinib, erlotinib, idelalisib and copanlisib are quinazoline-based, FDA-approved PI3K inhibitors, while compounds like NVPBYL719, GDC-0032, AZD8186, AZD-6482, etc. are under different stages of clinical trials. In light of the above-mentioned facts, in the present study, we have reported different synthetic approaches, mechanisms of anticancer action, and structure-activity relationship analysis of reported quinazoline derivatives as PI3K inhibitors to help researchers working in the field in designing better and isoform-selective PI3K inhibitors.

Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.