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Synthetic Dihydropyridines as Novel Antiacanthamoebic Agents

Anwar A, Siddiqui R, Hameed A, Shah MR, Khan NA

Med Chem, 2020;16(7):841-847.
PMID: 31544702 DOI: 10.2174/1573406415666190722113412

BACKGROUND: Acanthamoeba is an opportunistic pathogen widely spread in the environment. Acanthamoeba causes excruciating keratitis which can lead to blindness. The lack of effective drugs and its ability to form highly resistant cyst are one of the foremost limitations against successful prognosis. Current treatment involves mixture of drugs at high doses but still recurrence of infection can occur due to ineffectiveness of drugs against the cyst form. Pyridine and its natural and synthetic derivatives are potential chemotherapeutic agents due to their diverse biological activities.
OBJECTIVE: To study the antiamoebic effects of four novel synthetic dihydropyridine (DHP) compounds against Acanthamoeba castellanii belonging to the T4 genotype. Furthermore, to evaluate their activity against amoeba-mediated host cells cytopathogenicity as well as their cytotoxicity against human cells.
METHODS: Dihydropyridines were synthesized by cyclic dimerization of alkylidene malononitrile derivatives. Four analogues of functionally diverse DHPs were tested against Acanthamoeba castellanii by using amoebicidal, encystation and excystation assays. Moreover, Lactate dehydrogenase assays were carried out to study cytopathogenicity and cytotoxicity against human cells.
RESULTS: These compounds showed significant amoebicidal and cysticidal effects at 50 μM concentration, whereas, two of the DHP derivatives also significantly reduced Acanthamoebamediated host cell cytotoxicity. Moreover, these DHPs were found to have low cytotoxicity against human cells suggesting a good safety profile.
CONCLUSION: The results suggest that DHPs have potential against Acanthamoeba especially against the more resistant cyst stage and can be assessed further for drug development.

Matched MeSH terms: Dihydropyridines/pharmacology*
Molecular basis for resistance to ACCase-inhibiting fluazifop in Eleusine indica from Malaysia

Cha TS, Najihah MG, Sahid IB, Chuah TS

Pestic Biochem Physiol, 2014 May;111:7-13.
PMID: 24861927 DOI: 10.1016/j.pestbp.2014.04.011

Eleusine indica (goosegrass) populations resistant to fluazifop, an acetyl-CoA carboxylase (ACCase: EC6.4.1.2)-inhibiting herbicide, were found in several states in Malaysia. Dose-response assay indicated a resistance factor of 87.5, 62.5 and 150 for biotypes P2, P3 and P4, respectively. DNA sequencing and allele-specific PCR revealed that both biotypes P2 and P3 exhibit a single non-synonymous point mutation from TGG to TGC that leads to a well known Trp-2027-Cys mutation. Interestingly, the highly resistant biotype, P4, did not contain any of the known mutation except the newly discovered target point Asn-2097-Asp, which resulted from a nucleotide change in the codon AAT to GAT. ACCase gene expression was found differentially regulated in the susceptible biotype (P1) and highly resistant biotype P4 from 24 to 72h after treatment (HAT) when being treated with the recommended field rate (198gha(-1)) of fluazifop. However, the small and erratic differences of ACCase gene expression between biotype P1 and P4 does not support the 150-fold resistance in biotype P4. Therefore, the involvement of the target point Asn-2097-Asp and other non-target-site-based resistance mechanisms in the biotype P4 could not be ruled out.

Matched MeSH terms: Dihydropyridines/pharmacology*
The role of multifunctional drug therapy as an antidote to combat experimental subacute neurotoxicity induced by organophosphate pesticides

Singh S, Prakash A, Kaur S, Ming LC, Mani V, Majeed AB

Environ Toxicol, 2016 Aug;31(8):1017-26.
PMID: 25864908 DOI: 10.1002/tox.22111

Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leading to a massive build-up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioral deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioral problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single-agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioral studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1017-1026, 2016.

Matched MeSH terms: Dihydropyridines/pharmacology*
Fulltext In-VITRo effect of Ficus deltoidea on the contraction of isolated rat's uteri is mediated via multiple receptors binding and is dependent on extracellular calcium

Salleh N, Ahmad VN

BMC Complement Altern Med, 2013 Dec 14;13:359.
PMID: 24330515 DOI: 10.1186/1472-6882-13-359

BACKGROUND: Ficus deltoidea, is a perennial herb that is used to assist labor, firm the uterus post-delivery and to prevent postpartum bleeding. In view of its claimed uterotonic action, the mechanisms underlying plant's effect on uterine contraction were investigated.
METHODS: Adult female SD rats were injected with 2 mg/kg 17β-oestradiol (E2) to synchronize their oestrous cycle. A day after injection, uteri were removed for in-vitro contraction studies. The dose dependent effect of Ficus deltoidea aqeous extract (FDA) on the tension produced by the isolated rat's uteri was determined. The effects of atropine (2×10(-8) M), atosiban (0.5 IU), THG113.31 (10 μM), oxodipine (0.25 mM), EDTA (1 mM), 2-amino-ethoxy-diphenylborate (2-APB) (40 mM) and thapsigargin (1 mM) on the maximum force of contraction (Emax) achieved following 2 mg/ml FDA administration were also investigated.
RESULTS: FDA induced in-vitro contraction of the isolated rat's uteri in a dose-dependent manner. Administration of atropine, atosiban and THG113.31 reduced the Emax with atosiban having the greatest effect. The Emax was also reduced following oxodipine and EDTA administration. There was no significant change observed following 2-APB administration. Thapsigargin, however, augmented Emax.
CONCLUSIONS: FDA-induced contraction of the isolated rat's uteri is mediated via multiple uterotonin receptors (muscarinic, oxytocin and prostaglandin F2α) and was dependent on the extracellular Ca2+. Contraction, however, was not dependent on the Ca2+ release from the internal stores. This in-vitro study provides the first scientific evidence on the claimed effect of Ficus Deltoidea on uterine contraction.

Matched MeSH terms: Dihydropyridines/pharmacology