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Novel Phytochemical Constituents and their Potential to Manage Diabetes

Khalivulla SI, Mohammed A, Mallikarjuna K

Curr Pharm Des, 2021;27(6):775-788.
PMID: 33355047 DOI: 10.2174/1381612826666201222154159

BACKGROUND: Diabetes is a chronic disease affecting a large population worldwide and stands as one of the major global health challenges to be tackled. According to World Health Organization, about 400 million are having diabetes worldwide and it is the seventh leading cause of deaths in 2016. Plant-based natural products have been in use from ancient times as ethnomedicine for the treatment of several diseases, including diabetes. As a result of that, there are several reports on plant-based natural products displaying antidiabetic activity. In the current review, such antidiabetic potential compounds reported from all plant sources along with their chemical structures are collected, presented and discussed. These kinds of reports are essential to pool the available information to one source, followed by statistical analysis and screening to check the efficacy of all known compounds in a comparative sense. This kind of analysis can give rise to a few potential compounds from hundreds, which can further be screened through in vitro and in vivo studies, and human trails leading to the drug development.
METHODS: Phytochemicals, along with their potential antidiabetic property, were classified according to their basic chemical skeleton. The chemical structures of all the compounds with antidiabetic activities were elucidated in the present review. In addition to this, the distribution and their other remarkable pharmacological activities of each species are also included.
RESULTS: The scrutiny of literature led to the identification of 44 plants with antidiabetic compounds (70) and other pharmacological activities. For the sake of information, the distribution of each species in the world is given. Many plant derivatives may exert anti-diabetic properties by improving or mimicking insulin production or action. Different classes of compounds including sulfur compounds (1-4), alkaloids (5-11), phenolic compounds (12-17), tannins (18-23), phenylpropanoids (24-27), xanthanoids (28-31), amino acid (32), stilbenoid (33), benzofuran (34), coumarin (35), flavonoids (36-49) and terpenoids (50-70) were found to be potential active compounds for antidiabetic activity. Of the 70 listed compounds, majorly 17 compounds are obtained from triterpenoids, 13 from flavonoids and 7 from alkaloids. Among all the 44 plant species, the maximum number (7) of compounds were isolated from Lagerstroemia speciosa followed by Momordica charantia (6) and S. oblonga with 5 compounds.
CONCLUSION: This is the first paper to summarize the established chemical structures of phytochemicals that have been successfully screened for antidiabetic potential and their mechanisms of inhibition. The reported compounds could be considered as potential lead molecules for the treatment of type-2 diabetes. Further, molecular and clinical trials are required to select and establish therapeutic drug candidates.
New flavan and alkyl alpha,beta-lactones from the stem bark of Horsfieldia superba

Al-Mekhlafi NA, Shaaria K, Abas F, Jeyaraj EJ, Stanslas J, Khalivulla SI, et al.

Nat Prod Commun, 2013 Apr;8(4):447-51.
PMID: 23738449

In the present study phytochemical investigation of the methanol extract of the stem bark of Horsfieldia superba led to the isolation of twenty compounds (1-20), of which three (1-3) were new. However, compounds 2 and 3 were previously reported as synthetic alpha,beta-lactones. The compounds were characterized as (-)-3,4',7-trihydroxy-3'-methoxyflavan (1), (-)-5,6-dihydro-6-undecyl-2H-pyran-2-one (2), and (-)-5,6-dihydro-6-tridecyl-2H-pyran-2-one (3). Seventeen other known compounds were also isolated and identified as (-)-viridiflorol (4), hexacosanoic acid (5), beta-sitosterol (6), methyl 2,4-dihydroxy-6-methylbenzoate (methylorsellinate) (7), methyl 2,4-dihydroxy-3,6-dimethylbenzoate (8), (-)-4'-hydroxy-7-methoxyflavan (9), (-)-4',7-dihydroxyflavan (10), (-)-4',7-dihydroxy-3'-methoxyflavan (11), (+)-3,4',7-trihydroxyflavan (12), (-)-catechin (13), (-)-epicatechin (14), (-)-7-hydroxy-3',4'-methylenedioxyflavan (15), 2',3,4-trihydroxy-4'-methoxydihydrochalcone (16), 3',4',7-trihydroxyflavone (17), (+)-4'-hydroxy-7-methoxyflavanone (18), hexadecanoic acid (palmitic acid) (19) and 3,4-dihydroxybenzoic acid (20). The structures of the compounds were fully characterized by various physical methods (melting point, optical rotation), spectral (UV, IR, ID and 2D NMR) and mass spectrometric techniques. In vitro assay of compounds 2 and 3 demonstrated moderate cytotoxic activities against human prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cells, while the chloroform and ethyl acetate fractions of H. superba were found to exhibit moderate AChE inhibitory activity (IC50 72 and 60 microg/mL).
Fulltext Synthesis of bisindolylmethanes and their cytotoxicity properties

Naidu KR, Khalivulla SI, Rasheed S, Fakurazi S, Arulselvan P, Lasekan O, et al.

Int J Mol Sci, 2013;14(1):1843-53.
PMID: 23325050 DOI: 10.3390/ijms14011843

Polymer supported dichlorophosphate (PEG-OPOCl(2)) is an efficient green catalyst for the electrophilic substitution reaction of indole with aromatic aldehydes, in neat condition, to afford an excellent yield of bis(indolyl) methanes with short reaction time, at room temperature. The synthesized compounds and their anti-cancer activity are evaluated.
Novel Phytochemical Constituents and Anticancer Activities of the Genus, Typhonium

Khalivulla SI, Mohammed A, Sirajudeen KNS, Shaik MI, Ye W, Korivi M

Curr Drug Metab, 2019;20(12):946-957.
PMID: 31744445 DOI: 10.2174/1389200220666191118102616

BACKGROUND: Typhonium is the largest genus in the Araceae family (~70 species), distributed in South Asia, Southeast Asia and Australia. Typhonium is well-known for its ethnopharmacological uses, and Southeast Asians consider it as an alternative medicine to treat cancer. This review elucidated the confirmed chemical structures of the isolated compounds of Typhonium and emphasized on their anticancer activities against various human cancer cells.
METHODS: Among several species, Typhonium blumei, T. flagelliforme, T. divaricatum and T. giganteum were extensively studied due to the presence of a class of secondary metabolites. All the available reports on Typhonium were included and discussed in this article.
RESULTS: Until now several groups of compounds, namely amino acids (1, 2), cinnamic acid (3), fatty acids (4-14), glycerol derivatives (15-18) and cerebrosides (19-34), flavonoids (35), hydantoins (36-38), lignin monomers (39-44), nucleobases (45-48), pheophorbides (49-52), phthalate (53), terpene and steroids (54-59) and vitamins (60, 61) were isolated and characterized from Typhonium. These phytochemicals were investigated for their anticancer properties, and results confirmed the promising growth inhibitory effect and anticancer activities against human lung, breast, prostate and colon cancer cells. The anticancer activity of these compounds appears to be mediated through the induction of apoptotic cell death. These phytochemicals further reported to exhibit other pharmacological efficacies, including anti-inflammatory, antioxidant, antiviral, anti-allergic, neuroprotective and hepato-protective properties.
CONCLUSION: This is the first review to summarize the anticancer properties of all isolated compounds of Typhonium genus with confirmed chemical structures. Further advanced studies are necessary to establish the detailed signaling pathways that are involved in the anticancer property of the compounds.
Anti-hyperalgesic effect of a benzilidine-cyclohexanone analogue on a mouse model of chronic constriction injury-induced neuropathic pain: Participation of the κ-opioid receptor and KATP

Ming-Tatt L, Khalivulla SI, Akhtar MN, Lajis N, Perimal EK, Akira A, et al.

Pharmacol. Biochem. Behav., 2013 Dec;114-115:58-63.
PMID: 24201054 DOI: 10.1016/j.pbb.2013.10.019

The present study investigated the analgesic effect of a novel synthetic cyclohexanone derivative, 2,6-bis-4-(hydroxyl-3-methoxybenzilidine)-cyclohexanone or BHMC in a mouse model of chronic constriction injury-induced neuropathic pain. It was demonstrated that intraperitoneal administration of BHMC (0.03, 0.1, 0.3 and 1.0mg/kg) exhibited dose-dependent inhibition of chronic constriction injury-induced neuropathic pain in mice, when evaluated using Randall-Selitto mechanical analgesiometer. It was also demonstrated that pretreatment of naloxone (non-selective opioid receptor blocker), nor-binaltorphimine (nor-BNI, selective κ-opioid receptor blocker), but not β-funaltrexamine (β-FN, selective μ-opioid receptor blocker) and naltrindole hydrochloride (NTI, selective δ-opioid receptor blocker), reversed the anti-nociceptive effect of BHMC. In addition, the analgesic effect of BHMC was also reverted by pretreatment of 1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ, soluble guanosyl cyclase blocker) and glibenclamide (ATP-sensitive potassium channel blocker) but not Nω-nitro-l-arginine (l-NAME, a nitric oxide synthase blocker). Taken together, the present study demonstrated that the systemic administration of BHMC attenuated chronic constriction, injury-induced neuropathic pain. We also suggested that the possible mechanisms include κ-opioid receptor activation and nitric oxide-independent cyclic guanosine monophosphate activation of ATP-sensitive potassium channel opening.
Fulltext Antinociceptive activity of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone, on nociception-induced models in mice

Ming-Tatt L, Khalivulla SI, Akhtar MN, Mohamad AS, Perimal EK, Khalid MH, et al.

Basic Clin Pharmacol Toxicol, 2012 Mar;110(3):275-82.
PMID: 21967232 DOI: 10.1111/j.1742-7843.2011.00804.x

This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), using chemical- and thermal-induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose-related inhibition in the acetic acid-induced abdominal constriction test in mice with an ID(50) of 0.15 (0.13-0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin-induced paw licking test with an ID(50) of 0.35 (0.27-0.46) mg/kg and 0.07 (0.06-0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot-plate test. Moreover, the antinociceptive effect of the BHMC in the formalin-induced paw licking test and the hot-plate test was antagonized by pre-treatment with the non-selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID(50) of 0.66 (0.41-1.07) mg/kg and 0.42 (0.38-0.51) mg/kg, respectively. Finally, it was also shown that BHMC-induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of various inflammatory mediators.
Fulltext Possible participation of nitric oxide/cyclic guanosine monophosphate/protein kinase C/ATP-sensitive K(+) channels pathway in the systemic antinociception of flavokawin B

Mohamad AS, Akhtar MN, Khalivulla SI, Perimal EK, Khalid MH, Ong HM, et al.

Basic Clin Pharmacol Toxicol, 2011 Jun;108(6):400-5.
PMID: 21214864 DOI: 10.1111/j.1742-7843.2010.00670.x

The possible mechanisms of action in the antinociceptive activity induced by systemic administration (intraperitoneal, i.p.) of flavokawin B (FKB) were analysed using chemical models of nociception in mice. It was demonstrated that i.p. administration of FKB to the mice at 0.3, 1.0, 3.0 and 10 mg/kg produced significant dose-related reduction in the number of abdominal constrictions. The antinociception induced by FKB in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with L-arginine, the substrate for nitric oxide synthase or glibenclamide, the ATP-sensitive K(+) channel inhibitor, but was enhanced by methylene blue, the non-specific guanylyl cyclase inhibitor. FKB also produced dose-dependent inhibition of licking response caused by intraplantar injection of phorbol 12-myristate 13-acetate, a protein kinase C activator (PKC). Together, these data indicate that the NO/cyclic guanosine monophosphate/PKC/ATP-sensitive K(+) channel pathway possibly participated in the antinociceptive action induced by FKB.