The manuscript titled “Quinolone-Sulfonamides as a Multi-targeting Neurotherapeutic for Cognitive Decline: In-vitro, In-silico studies and ADME evaluation of Monoamine Oxidases and Cholinesterases Inhibitors” describes the preparation of structural analogues of quinolone-sulfonamides and their monoamine oxidase and cholinesterase inhibition activities. The study is conducted in a reasonably systematic and planned fashion. Moreover, the overall organization and presentation of the manuscript is quite reasonable and justify its publication in the RSC Advances. Nevertheless, I would recommend the publication of this manuscript after incorporation of following major changes before its acceptance.
(a) Introduction: The perplexity and incoherence in the presentation of the contents together with very poor English language make this part very poor. The entire organization of the rational part is meagre and perplexed. The work presented is about the synthesis and monoamine oxidase and cholinesterase inhibitory activities of quinolone sulfonamides and the entire discussion should have been focused on the role of monoamine oxidase and cholinesterase enzymes in cognitive decline, past reports on the pharmacological activities of quinolone sulfonamides etc, which would allow bridging the research gap. For example, what is the role played by cholinesterase enzymes and why their inhibition is important? An enhanced AChE activity in early stages of the Alzheimer’s disease is one of the hallmarks that leads to decrease in acetylcholine (ACh) levels in the brain. The consequences of these features result in cholinergic dysfunction and neurodegeneration, which lead to memory and cognitive deficits. The problem description should be sufficiently explained in the introduction section. There are several statements that are perplexed and puzzling, just to cite a few “Cognitive disorder research into the causes and treatments is currently underway…”, “The molecular etiology of gliosis is assumed to involve…”, “Inhibiting enzymes such as monoamine oxidase and cholinesterase is the most effective way to treat CD”. The introduction needs extensive revision in the lines proposed above. Authors are encouraged to read earlier reported work on the subject (Arabian Journal of Chemistry (2021) 14, 103211).
(b). Figure 1: Caption needs to be changed to “Chemical structures of selected ChE and MAO inhibitors”
(c) Novelty is missing. The problem description and the novelty are not sufficiently explained or clear in the introduction section. Also, the researches gap should be clearly described
(d). 2.2. General procedure for the synthesis of quinoline-8-sulfonamide: delete the statement “In the current study, a series of new quinoline-8-sulfonamide derivatives (a1-18) was synthesized,
by treating quinoline-8-sulfonyl chloride (1) with substituted amines (2).” Also, include the quantities, molar ratios for all the reagents and reactants and percent yield obtained for the reaction. Pyridine can not be used as a catalyst in the reaction until excess amount of amines are used in these reactions.

(e) 2.2. Biological activity: unclear statement “absorbance-based assay with the substrate ptyramine, ATCCl and BTCCl based (also see Experimental Section and Supporting)” Information)

(f) The source of enzymes AChE and BChE (human, electric eel or horse) should be described.

(g) Structure-activity relationship study (SARs): It sounds like more a reporting writing, since it clearly lacks authors personnel scientific insights. Changes in activities associated with structural changes in the molecules needs to be elaborated upon and rationalized. Moreover, discussion about the SARs can be better followed when represented in a quantified manner. How many folds an activity of a compound is enhanced or diminished when changing a functionality or structure feature in a compound? This should be included in the discussion for a better understanding to readership.
(h) change figure 4 in the statement to figure 9 “toward MAO-A, MAO-B, AChE and BChE respectively as displayed in figure 4”.

(i) Despite the text is quite understandable, the language of the manuscript is sub-standard. Several grammatical errors present throughout the manuscript. It contains several puzzling and unclear sentences/statements. These should be fixed throughout the manuscript.

(j) Conclusions section should also be revised by adding few sentences to elaborate on the overall summary of the outcomes.